CN115850296A

CN115850296A - Crystal form of thienoimidazole compound and preparation method thereof

Info

Publication number: CN115850296A
Application number: CN202211537195.4A
Authority: CN
Inventors: 甘露; 于涛; 吴成德; 姚婷
Original assignee: Sciwind Biosciences Co Ltd
Current assignee: Sciwind Biosciences Co Ltd
Priority date: 2021-12-03
Filing date: 2022-12-02
Publication date: 2023-03-28
Also published as: WO2023098852A1; CA3239813A1

Abstract

A crystal form of a thienoimidazole compound and a preparation method thereof, and also comprises the application of the crystal form in preparing medicaments for treating related diseases.

Description

Crystal form of thienoimidazole compound and preparation method thereof

Technical Field

The invention relates to a crystal form of a thienoimidazole compound and a preparation method thereof, and also comprises application of the crystal form in preparation of medicaments for treating related diseases.

Background

Diabetes mellitus is a common metabolic disease characterized by hyperglycemia. Several major types of diabetes are caused by complex interactions between genetic and environmental factors. Factors causing hyperglycemia include a decrease in insulin secretion ability, a decrease in glucose utilization ability, and an increase in glucose output, which are mainly attributed to the cause of diabetes. Metabolic abnormalities associated with diabetes lead to secondary physio-physiological changes in multiple systems throughout the body. Long-term abnormal blood glucose levels can lead to serious complications, including cardiovascular disease, chronic renal failure, retinal damage, nerve damage, microvascular damage, obesity, and the like. The classification of diabetes is based on different pathological processes leading to hyperglycemia and can be divided into two main types, type 1 diabetes and type 2 diabetes. Type 1 and type 2 diabetes mellitus are characterized by abnormal glucose homeostasis prior to onset during the course of the disease. Type 1 diabetes is the result of complete or almost complete insulin deficiency. Type 2 diabetes is a heterogeneous group of diseases that manifest in varying degrees of insulin resistance, decreased insulin secretory function, and increased glucose production. Treatment of diabetes, early stage, diet control and exercise therapy are the preferred glycemic control regimens. When these methods are difficult to achieve blood glucose control, treatment with insulin or oral hypoglycemic drugs is required. Currently, drugs for the treatment of diabetes include insulin, insulin secretagogues, metformin, insulin sensitizers, α -glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors (statins), sodium-glucose co-transporter (SGLT 2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists, and the like. These drugs have good therapeutic effects, but have safety problems in long-term treatment, for example, biguanides are liable to cause lactic acidosis; sulfonylureas can cause hypoglycemic symptoms; insulin sensitizers can cause edema, heart failure and weight gain; alpha-glucosidase inhibitors can cause symptoms such as abdominal pain, abdominal distension, diarrhea, and the like; sodium-glucose co-transporter (SGLT 2) inhibitors increase the risk of urinary, reproductive infections, and the like. Therefore, a safer and more effective novel hypoglycemic medicament is urgently needed to be developed to meet the treatment requirement of diabetes.

The glucagon-like peptide-1 receptor (GLP-1R) is one of the most important therapeutic targets for type 2 diabetes. GLP-1R belongs to a member of the B cluster subfamily of G protein coupled receptors and is widely expressed in tissues such as stomach, small intestine, heart, kidney, lung, brain and the like in vivo. In islet cells, GLP-1R is mainly used for promoting the release of insulin, increasing the regeneration of islet B cells, inhibiting the apoptosis of B cells and reducing the release of glucagon. In tissues such as the gastrointestinal tract, GLP-1R can inhibit the peristalsis and gastric fluid secretion of the gastrointestinal tract by combining with an agonist thereof, delay gastric emptying and increase satiety. In neural tissue, small molecule GLP-1R agonists can penetrate through the brain to activate the neuron subset expressed by GLP-1R, protect the apoptosis of nerve cells and strengthen the learning and memory ability. Moreover, GLP-1R also controls food intake to reduce body weight. GLP-1 receptor agonists or endogenous GLP-1 activity enhancers are approved for the treatment of type 2 diabetes. Such drugs do not cause hypoglycemia because secretin-stimulated insulin secretion is glucose-dependent. Exenatide is an artificially synthesized peptide, originally found in lizard saliva, which is a GLP-1 analog. Exenatide has a different amino acid sequence compared to native GLP-1, making exenatide resistant to enzymes that degrade GLP-1 [ dipeptidyl peptidase IV (DPP-IV) ]. Therefore, exenatide has a prolonged GLP-1 like activity and can bind to GLP-1 receptors in the pancreatic islets, gastrointestinal tract, brain. Liraglutide, another GLP-1 receptor agonist, is almost identical to native GLP-1 except that it replaces one of the amino acids and adds a fatty acyl group, which promotes its binding to albumin and plasma proteins and prolongs half-life. GLP-1 receptor agonists increase glucose-stimulated insulin secretion, inhibit glucagon, and delay gastric emptying. These drugs do not increase body weight, and in fact, most patients experience some degree of weight loss and loss of appetite. DPP-IV inhibitors inhibit the degradation of native GLP-1, thereby enhancing the effect of secretin. DPP-IV, which is well expressed on the cell surface of endothelial cells and some lymphocytes, can degrade a wide variety of polypeptides (not only GLP-1). DPP-IV inhibitors promote insulin secretion without lowering blood glucose, without increasing body weight, and are more advantageous in lowering postprandial blood glucose. Patients with GLP-1 receptor agonists have higher levels of GLP-1 effect in vivo than patients with DPP-IV inhibitors.

The small molecule GLP-1 receptor stimulant with oral activity is developed, long-term self injection of patients can be effectively avoided, and good compliance is achieved. The small molecule GLP-1 receptor stimulant controls blood sugar through a plurality of ways of glucose metabolism and excretion, and is expected to develop a safer and more effective novel blood sugar reducing medicine to meet the treatment requirement of diabetes.

Disclosure of Invention

The present invention provides pharmaceutically acceptable salts of compounds of formula (O),

wherein the pharmaceutically acceptable salt is selected from tromethamine salt, phosphate, citrate, oxalate, maleate, L-tartrate, p-toluenesulfonate N, sodium salt, potassium salt, L-arginine salt, hydroxycholine salt, meglumine salt, preferably tromethamine salt, phosphate, oxalate, maleate, p-toluenesulfonate N, L-arginine salt, meglumine salt, more preferably tromethamine salt, meglumine salt.

In some embodiments of the invention, the chemical molar ratio of the compound to the acid or base molecule is 1: 2-2: 1, for example, may be 2: 3. 3: 4. 4: 5. 1: 1. 5: 4. 4: 3. 3:2, in some embodiments, the chemical molar ratio is preferably 1: 2. 1: 1. 2:1.

the present invention provides a process for preparing the above pharmaceutically acceptable salts, comprising: a step of salifying the compound of formula (I) with an acid or a base.

In some embodiments of the invention, the solvent used for the salt-forming reaction is selected from: at least one of butanone, methanol, ethanol, tetrahydrofuran, ethyl acetate, isopropanol, acetonitrile, and methyl tert-butyl ether.

The invention provides a medicinal composition which contains the medicinal salt and optional pharmaceutically acceptable carriers and excipients.

In some embodiments of the present invention, the above-mentioned pharmaceutically acceptable salt is used for the preparation of a medicament for the prevention and/or treatment of metabolic diseases, preferably diabetes, obesity, non-alcoholic fatty liver disease.

The present invention provides compounds of formula (II)

Wherein n is selected from 0 to 12, and for example may be 0, 1/2, 2/3, 1, 2, 2.7, 3, 4, 5, 6, 7, 8, in some embodiments of the invention n is selected from 0 to 5, in some embodiments of the invention n is selected from 0 to 3.

In some embodiments of the invention, n is selected from 0, 1/2, 2/3, 1, 2, 2.7, and 3.

In some embodiments of the invention, the compound of formula (II) has the structure,

the invention provides a crystal form A of a compound of a formula (II-1), which is characterized in that an X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 theta angles: 11.1426 +/-0.2000 degrees, 14.4804 +/-0.2000 degrees and 21.4921 +/-0.2000 degrees.

In some embodiments of the invention, the form a has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 11.1426 +/-0.2000 degrees, 14.4804 +/-0.2000 degrees, 17.7642 +/-0.2000 degrees, 19.6235 +/-0.2000 degrees and 21.4921 +/-0.2000 degrees.

In some embodiments of the present invention, the above form a has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 11.1426 +/-0.2000 degrees, 14.4804 +/-0.2000 degrees, 17.0921 +/-0.2000 degrees, 17.7642 +/-0.2000 degrees, 19.6235 +/-0.2000 degrees, 20.4359 +/-0.2000 degrees, 21.4921 +/-0.2000 degrees and 22.8874 +/-0.2000 degrees.

In some embodiments of the present invention, the above form a has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.6759 °,10.2572 °,11.1426 °,14.4804 °,16.2701 °,17.0921 °,17.7642 °,19.6235 °,20.4359 °,20.9310 °,21.4921 °,22.8874 °,25.1971 °,26.5995 °,27.9955 °,28.6836 °,29.4212 °,30.9896 °.

In some embodiments of the invention, the form a has an XRPD pattern substantially as shown in figure 1.

In some embodiments of the invention, the XRPD pattern analysis data for form a above is shown in table 1:

TABLE 1 XRPD pattern analysis data for compound form A of formula (II-1)

In some embodiments of the present invention, the differential scanning calorimetry curve of form a has peaks at an endothermic peak at 76.0 ± 3.0 ℃ and 130.3 ± 3.0 ℃, respectively.

In some embodiments of the invention, the DSC profile of form a above is substantially as shown in figure 2.

In some embodiments of the invention, the thermogravimetric analysis curve of form a above has a weight loss of 2.43% at 150.0 ± 3.0 ℃.

In some embodiments of the invention, the TGA profile of the form a is substantially as shown in figure 3.

The invention provides a crystal form B of a compound shown as a formula (II), which is characterized in that an X-ray powder diffraction pattern of the crystal form B has characteristic diffraction peaks at the following 2 theta angles: 13.3946 +/-0.2000 degrees, 16.0867 +/-0.2000 degrees and 18.7923 +/-0.2000 degrees.

In some embodiments of the invention, the form B has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.3578 +/-0.2000 degrees, 10.7076 +/-0.2000 degrees, 13.3946 +/-0.2000 degrees, 16.0867 +/-0.2000 degrees and 18.7923 +/-0.2000 degrees.

In some embodiments of the invention, the form B has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.3578 plus or minus 0.2000 degrees, 10.7076 plus or minus 0.2000 degrees, 13.3946 plus or minus 0.2000 degrees, 16.0867 plus or minus 0.2000 degrees, 18.7923 plus or minus 0.2000 degrees and 26.9882 plus or minus 0.2000 degrees.

In some embodiments of the invention, the form B has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.3578 °,10.7076 °,13.3946 °,16.0867 °,17.2158 °,18.7923 °,20.0218 °,20.7079 °,21.5030 °,23.0606 °,24.3029 °,25.5466 °,26.9882 °,28.4762 °,29.7465 °,30.8461 °,32.5003 °,35.2977 °,37.0829 °,38.1654 °.

In some embodiments of the invention, the form B has an XRPD pattern substantially as shown in figure 4.

In some embodiments of the invention, the XRPD pattern analysis data for form B above is shown in table 2:

table 2 XRPD pattern analysis data for compound form B of formula (II)

The invention provides a crystal form C of a compound shown in a formula (II), which is characterized in that an X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at the following 2 theta angles: 5.2235 +/-0.2000 deg, 13.0633 +/-0.2000 deg and 18.3202 +/-0.2000 deg.

In some embodiments of the invention, the above form C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.2235 +/-0.2000 deg, 13.0633 +/-0.2000 deg, 18.3202 +/-0.2000 deg, 19.0603 +/-0.2000 deg and 20.9687 +/-0.2000 deg.

In some embodiments of the invention, the above form C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.2235 +/-0.2000 degrees, 10.6330 +/-0.2000 degrees, 13.0633 +/-0.2000 degrees, 18.3202 +/-0.2000 degrees, 19.0603 +/-0.2000 degrees, 20.9687 +/-0.2000 degrees, 23.0438 +/-0.2000 degrees and 23.6332 +/-0.2000 degrees.

In some embodiments of the invention, the above form C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.2235 °,10.2060 °,10.4366 °,10.6330 °,11.6394 °,13.0633 °,16.3161 °,16.8840 °,17.9453 °,18.3202 °,19.0603 °,19.6631 °,20.5231 °,20.9687 °,21.3445 °,21.9752 °,22.4037 °,23.0438 °,23.3931 °,23.6332 °,23.9781 °,24.7774 °,25.4626 °,26.2681 °,26.7514 °,28.0533 °,28.9221 °,29.4437 °,30.4397 °,30.9179 °,32.6038 °,34.3656 °,36.3357 °,37.4691 °.

In some embodiments of the invention, the form C above has an XRPD pattern substantially as shown in figure 5.

In some embodiments of the invention, XRPD pattern analysis data for form C above is shown in table 3:

TABLE 3 XRPD pattern analysis data for form C of compound of formula (II)

The invention provides a crystal form D of a compound of formula (II), which is characterized in that an X-ray powder diffraction pattern of the crystal form D has characteristic diffraction peaks at the following 2 theta angles: 5.4120 +/-0.2000 degrees, 13.5502 +/-0.2000 degrees and 24.5140 +/-0.2000 degrees.

In some embodiments of the invention, the form D has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.4120 +/-0.2000 degrees, 8.1209 +/-0.2000 degrees, 13.5502 +/-0.2000 degrees, 16.2767 +/-0.2000 degrees and 24.5140 +/-0.2000 degrees.

In some embodiments of the invention, the form D has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.4120 +/-0.2000 degrees, 8.1209 +/-0.2000 degrees, 13.5502 +/-0.2000 degrees, 16.2767 +/-0.2000 degrees, 18.9363 +/-0.2000 degrees, 20.4857 +/-0.2000 degrees, 21.7578 +/-0.2000 degrees and 24.5140 +/-0.2000 degrees.

In some embodiments of the invention, the form D has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.4120 °,8.1209 °,10.4811 °,10.8250 °,11.4035 °,12.8266 °,13.5502 °,14.6390 °,16.2767 °,17.3099 °,17.6879 °,18.9363 °,20.4857 °,20.9317 °,21.4104 °,21.7578 °,21.9895 °,22.3592 °,22.9155 °,23.6785 °,24.5140 °,25.0791 °,25.8055 °,26.2813 °,27.7237 °,29.5078 °,30.9747 °,36.0140 °,36.8748 °.

In some embodiments of the invention, the form D has an XRPD pattern substantially as shown in figure 6.

In some embodiments of the invention, XRPD pattern analysis data for form D above is shown in table 4:

table 4 XRPD pattern analysis data for form D of compound of formula (II)

The invention provides a crystal form E of a compound shown as a formula (II), which is characterized in that an X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at the following 2 theta angles: 18.8216 +/-0.2000 degrees, 20.0568 +/-0.2000 degrees and 25.1936 +/-0.2000 degrees.

In some embodiments of the invention, the above form E has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 10.8415 +/-0.2000 degrees, 13.3963 +/-0.2000 degrees, 18.8216 +/-0.2000 degrees, 20.0568 +/-0.2000 degrees and 25.1936 +/-0.2000 degrees.

In some embodiments of the invention, the above form E has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 10.3742 +/-0.2000 degrees, 10.8415 +/-0.2000 degrees, 13.3963 +/-0.2000 degrees, 16.1259 +/-0.2000 degrees, 18.8216 +/-0.2000 degrees, 20.0568 +/-0.2000 degrees, 20.7958 +/-0.2000 degrees and 25.1936 +/-0.2000 degrees.

The invention provides a crystal form E of a compound shown as a formula (II), which is characterized in that an X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at the following 2 theta angles: 18.8216 + -0.2000 deg., 20.0568 + -0.2000 deg., and/or 25.1936 + -0.2000 deg., and/or 10.8415 + -0.2000 deg., and/or 13.3963 + -0.2000 deg., and/or 10.3742 + -0.2000 deg., and/or 16.1259 + -0.2000 deg., and/or 20.7958 + -0.2000 deg., and/or 5.3759 + -0.2000 deg., and/or 11.5008 + -0.2000 deg., and/or 15.7418 + -0.2000 deg., and/or 16.6392 + -0.2000 deg., and/or 17.2881 + -0.2000 deg., and/or 19.2577 + -0.2000 deg., and/or 21.4850 + -0.2000 deg., and/or 16.6392 + -0.2000 deg., and/or 17. and/or 22.1639 +/-0.2000 deg., and/or 23.0777 +/-0.2000 deg., and/or 24.1467 +/-0.2000 deg., and/or 24.6828 +/-0.2000 deg., and/or 25.5960 +/-0.2000 deg., and/or 26.2392 +/-0.2000 deg., and/or 26.7365 +/-0.2000 deg., and/or 27.1146 +/-0.2000 deg., and/or 27.8176 +/-0.2000 deg., and/or 28.5679 +/-0.2000 deg., and/or 29.6443 +/-0.2000 deg., and/or 30.8753 +/-0.2000 deg., and/or 33.0123 +/-0.2000 deg., and/or 33.8173 +/-0.2000 deg., and/or 36.5754 +/-0.2000 deg..

In some embodiments of the invention, the above form E has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.3759 deg., 10.3742 deg., 10.8415 deg., 11.5008 deg., 13.3963 deg., 15.7418 deg., 16.1259 deg., 16.6392 deg., 17.2881 deg., 18.8216 deg., 19.2577 deg., 20.0568 deg., 20.7958 deg., 21.4850 deg., 22.1639 deg., 23.0777 deg., 24.1467 deg., 24.6828 deg., 25.1936 deg., 25.5960 deg., 26.2392 deg., 26.7365 deg., 27.1146 deg., 27.8176 deg., 28.5679 deg., 29.6443 deg., 30.8753 deg., 33.0123 deg., 33.8173 deg., 36.5754 deg..

In some embodiments of the invention, the form E above has an XRPD pattern substantially as shown in figure 7.

In some embodiments of the invention, the XRPD pattern analysis data for form E above is shown in table 5:

TABLE 5 XRPD pattern analysis data for Compound form E of formula (II)

In some embodiments of the invention, the above-mentioned differential scanning calorimetry curve of the E crystal form has a peak with an endothermic peak at 91.0 ± 3.0 ℃ and 149.9 ± 3.0 ℃, respectively.

In some embodiments of the invention, the DSC profile of form E above is substantially as shown in figure 8.

In some embodiments of the invention, the thermogravimetric analysis curve of form E above has a weight loss of 6.37% at 150.0 ± 3.0 ℃.

In some embodiments of the invention, the TGA profile of the crystalline form E described above is substantially as shown in figure 9. The invention provides a crystal form F of a compound shown as a formula (II), which is characterized in that an X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at the following 2 theta angles: 5.4518 +/-0.2000 deg., 19.3372 +/-0.2000 deg. and 20.6984 +/-0.2000 deg..

In some embodiments of the invention, the crystalline form F has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.4518 +/-0.2000 degrees, 10.5789 +/-0.2000 degrees, 16.4789 +/-0.2000 degrees, 19.3372 +/-0.2000 degrees and 20.6985 +/-0.2000 degrees.

In some embodiments of the invention, the crystalline form F has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.4518 +/-0.2000 degrees, 10.5789 +/-0.2000 degrees, 16.4789 +/-0.2000 degrees, 17.7935 +/-0.2000 degrees, 19.3372 +/-0.2000 degrees, 20.6985 +/-0.2000 degrees, 22.3282 +/-0.2000 degrees and 26.3477 +/-0.2000 degrees.

In some embodiments of the invention, the crystalline form F has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.4518 °,10.5789 °,11.5837 °,13.0825 °,13.6602 °,14.9423 °,16.4789 °,17.7935 °,19.3372 °,20.6984 °,21.2538 °,22.3282 °,24.7246 °,26.3477 °,27.4475 °,28.7110 °.

In some embodiments of the invention, the form F above has an XRPD pattern substantially as shown in figure 10.

In some embodiments of the invention, XRPD pattern analysis data for the form F is shown in table 6:

TABLE 6 XRPD pattern analysis data for crystalline form F of compound of formula (II)

The invention provides a crystal form G of a compound of formula (II), which is characterized in that an X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2 theta angles: 13.2453 +/-0.2000 deg., 18.1001 +/-0.2000 deg., 20.5915 +/-0.2000 deg.

In some embodiments of the invention, the above form G has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.3356 +/-0.2000 degrees, 13.2453 +/-0.2000 degrees, 18.1001 +/-0.2000 degrees, 19.3293 +/-0.2000 degrees and 20.5915 +/-0.2000 degrees.

In some embodiments of the invention, the above form G has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.3356 +/-0.2000 degrees, 13.2453 +/-0.2000 degrees, 18.1001 +/-0.2000 degrees, 18.5528 +/-0.2000 degrees, 19.3293 +/-0.2000 degrees, 19.7622 +/-0.2000 degrees, 20.5915 +/-0.2000 degrees and 23.5540 +/-0.2000 degrees.

In some embodiments of the invention, the above form G has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.3356 °,10.7072 °,13.2453 °,14.9037 °,16.6883 °,18.1001 °,18.5528 °,19.3293 °,19.7622 °,20.5915 °,21.3864 °,22.0249 °,22.5324 °,23.1856 °,23.5540 °,24.9841 °,25.5102 °,26.9502 °,28.1389 °,29.0651 °,30.3926 °.

In some embodiments of the invention, the form G above has an XRPD pattern as substantially depicted in figure 11.

In some embodiments of the invention, the XRPD pattern analysis data for the form G is shown in table 7:

TABLE 7 XRPD pattern analysis data for form G of compound of formula (II)

The invention provides a compound of formula (II) in crystal form H, which is characterized in that the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.2142 +/-0.2000 degrees, 9.2475 +/-0.2000 degrees, 17.8933 +/-0.2000 degrees.

In some embodiments of the invention, the above form H has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.2142 +/-0.2000 degrees, 9.2475 +/-0.2000 degrees, 17.8933 +/-0.2000 degrees, 22.0544 +/-0.2000 degrees and 23.0224 +/-0.2000 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above form H has characteristic diffraction peaks at the following 2 Θ angles: 5.2142 +/-0.2000 degrees, 9.2475 +/-0.2000 degrees, 17.8933 +/-0.2000 degrees, 19.3686 +/-0.2000 degrees, 20.2031 +/-0.2000 degrees, 21.2391 +/-0.2000 degrees, 22.0544 +/-0.2000 degrees and 23.0224 +/-0.2000 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above form H has characteristic diffraction peaks at the following 2 Θ angles: 5.2142 °,9.2475 °,10.2712 °,13.6133 °,15.5872 °,16.1306 °,17.8933 °,18.7847 °,19.3686 °,20.2031 °,20.7049 °,21.2391 °,22.0544 °,23.0224 °,24.1930 °,26.9749 °.

In some embodiments of the invention, the form H has an XRPD pattern substantially as shown in figure 12.

In some embodiments of the invention, XRPD pattern analysis data for the above form H is shown in table 8:

TABLE 8 XRPD pattern analysis data for form H of compound of formula (II)

The invention provides a crystal form I of a compound shown as a formula (II), which is characterized in that an X-ray powder diffraction pattern of the crystal form I has characteristic diffraction peaks at the following 2 theta angles: 5.1906 +/-0.2000 deg. 12.9022 +/-0.2000 deg. 15.4944 +/-0.2000 deg.

In some embodiments of the invention, the above form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.1906 +/-0.2000 degrees, 10.3443 +/-0.2000 degrees, 12.9022 +/-0.2000 degrees, 15.4944 +/-0.2000 degrees and 18.08160.2000 degrees.

In some embodiments of the invention, the above form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.1906 +/-0.2000 deg., 10.3443 +/-0.2000 deg., 12.9022 +/-0.2000 deg., 13.4027 +/-0.2000 deg., 15.4944 +/-0.2000 deg., 16.1068 +/-0.2000 deg., 18.0816 +/-0.2000 deg., 18.8121 +/-0.2000 deg..

In some embodiments of the invention, the above form I has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.1906 °,7.7331 °,10.3443 °,10.7143 °,12.9022 °,13.4027 °,15.4944 °,16.1068 °,18.0816 °,18.8121 °,23.3219 °,26.9651 °,28.5725 °.

In some embodiments of the invention, the form I above has an XRPD pattern substantially as shown in figure 13.

In some embodiments of the invention, the XRPD pattern analysis data for form I above is shown in table 9:

TABLE 9 XRPD pattern analysis data for the crystalline form of compound I of formula (II)

The invention also provides compounds of formula (III),

wherein i is selected from 0 to 2, and may be, for example, 0, 1/2, 2/3, 1, 1.5 or 2.

The invention provides a crystal form J of a compound of formula (III), which is characterized in that an X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2 theta angles: 6.763 plus or minus 0.200 degrees, 13.619 plus or minus 0.200 degrees, 18.128 plus or minus 0.200 degrees.

In some embodiments of the invention, the crystalline form J has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.763 plus or minus 0.200 degrees, 13.619 plus or minus 0.200 degrees, 15.848 plus or minus 0.200 degrees, 18.128 plus or minus 0.200 degrees and 24.643 plus or minus 0.200 degrees.

In some embodiments of the invention, the crystalline form J has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.763 plus or minus 0.200 degrees, 13.619 plus or minus 0.200 degrees, 15.848 plus or minus 0.200 degrees, 18.128 plus or minus 0.200 degrees, 19.438 plus or minus 0.200 degrees, 21.422 plus or minus 0.200 degrees, 22.621 plus or minus 0.200 degrees, 24.643 plus or minus 0.200 degrees.

In some embodiments of the invention, the crystalline form J has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.763 °,9.065 °,9.535 °,11.902 °,12.066 °,12.874 °,13.619 °,14.169 °,14.918 °,15.848 °,16.105 °,16.573 °,17.620 °,18.128 °,18.510 °,18.826 °,19.107 °,19.438 °,20.538 °,21.191 °,21.422 °,21.794 °,22.416 °,22.621 °,22.806 °,23.376 °,23.609 °,24.643 °,25.149 °,25.650 °,27.329 °, 28.368 °,29.916 °,30.162 °,31.416 °,33.040 °,33.684 °,35.327 °,37.570 °.

In some embodiments of the invention, the form J above has an XRPD pattern substantially as shown in figure 14.

In some embodiments of the invention, XRPD pattern analysis data for the above form J is shown in table 10:

table 10 XRPD pattern analysis data for compound form J of formula (III)

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The invention also provides compounds of formula (IV),

wherein m is selected from 0 to 2, and may be, for example, 0, 1/2, 2/3, 1, 1.5 or 2.

In some embodiments of the invention, the compound of formula (IV) has the structure,

the invention provides a K crystal form of a compound shown as a formula (IV-1), which is characterized in that an X-ray powder diffraction pattern of the K crystal form has characteristic diffraction peaks at the following 2 theta angles: 16.860 +/-0.200 degrees, 18.189 +/-0.200 degrees and 20.709 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above form K has characteristic diffraction peaks at the following 2 Θ angles: 9.972 +/-0.200 degrees, 16.860 +/-0.200 degrees, 18.189 +/-0.200 degrees, 20.709 +/-0.200 degrees and 23.950 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above form K has characteristic diffraction peaks at the following 2 Θ angles: 4.581 +/-0.200 degrees, 9.972 +/-0.200 degrees, 10.392 +/-0.200 degrees, 16.860 +/-0.200 degrees, 18.189 +/-0.200 degrees, 20.709 +/-0.200 degrees, 23.950 +/-0.200 degrees and 26.841 +/-0.200 degrees.

In some embodiments of the invention, the crystalline form K has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 4.581 °,6.439 °,9.972 °,10.232 °,10.392 °,13.328 °,14.053 °,14.696 °,16.860 °,18.189 °,20.709 °,22.766 °,23.950 °,25.785 °,26.841 °.

In some embodiments of the invention, the form K above has an XRPD pattern substantially as shown in figure 15.

In some embodiments of the invention, XRPD pattern analysis data for the above form K is shown in table 11:

TABLE 11 XRPD pattern analysis data for form K of compound of formula (IV-1)

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The invention provides a crystal form L of a compound of formula (IV), which is characterized in that an X-ray powder diffraction pattern of the crystal form L has characteristic diffraction peaks at the following 2 theta angles: 18.726 plus or minus 0.200 degrees, 21.044 plus or minus 0.200 degrees, 24.648 plus or minus 0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2 Θ angles: 6.494 plus or minus 0.200 degree, 18.726 plus or minus 0.200 degree, 19.547 plus or minus 0.200 degree, 21.044 plus or minus 0.200 degree and 24.648 plus or minus 0.200 degree.

In some embodiments of the invention, the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2 Θ angles: 6.494 +/-0.200 degrees, 15.366 +/-0.200 degrees, 17.885 +/-0.200 degrees, 18.726 +/-0.200 degrees, 19.547 +/-0.200 degrees, 21.044 +/-0.200 degrees, 24.648 +/-0.200 degrees and 27.453 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the crystalline form L has characteristic diffraction peaks at the following 2 Θ angles: 5.797 °,6.494 °,7.655 °,10.474 °,13.036 °,13.388 °,15.366 °,16.235 °,17.885 °,18.726 °,19.547 °,21.044 °,24.368 °,24.648 °,27.453 °.

In some embodiments of the invention, the form L is substantially as shown in figure 16 with an XRPD pattern.

In some embodiments of the invention, the XRPD pattern analysis data for the above form L is shown in table 12:

TABLE 12 XRPD pattern analysis data for the crystalline form L of compound of formula (IV)

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The invention also provides compounds of formula (V),

wherein o is selected from 0 to 2, and may be, for example, 0, 1/2, 2/3, 1, 1.5 or 2.

The invention provides a compound of formula (V) in the M crystal form, which is characterized in that the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.682 +/-0.200 degrees, 11.389 +/-0.200 degrees and 17.202 +/-0.200 degrees.

In some embodiments of the invention, the above form M has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.682 +/-0.200 degrees, 11.389 +/-0.200 degrees, 16.009 +/-0.200 degrees, 17.202 +/-0.200 degrees and 29.418 +/-0.200 degrees.

In some embodiments of the invention, the above M crystalline form has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.682 +/-0.200 degrees, 11.389 +/-0.200 degrees, 16.009 +/-0.200 degrees, 17.202 +/-0.200 degrees, 17.854 +/-0.200 degrees, 24.147 +/-0.200 degrees, 25.302 +/-0.200 degrees and 29.418 +/-0.200 degrees.

In some embodiments of the invention, the above M crystalline form has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.682 °,10.619 °,11.389 °,12.280 °,12.637 °,14.434 °,15.764 °,16.009 °,17.202 °,17.854 °,18.783 °,19.352 °,20.673 °,21.044 °,21.729 °,22.632 °,23.341 °,24.147 °,25.302 °,26.982 °,28.950 °,29.418 °,30.123 °,33.086 °.

In some embodiments of the invention, the crystalline form M described above has an XRPD pattern substantially as shown in figure 17.

In some embodiments of the invention, the XRPD pattern analysis data for the above form M is shown in table 13:

TABLE 13 XRPD pattern analysis data for form M of compound of formula (V)

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The invention also provides compounds of formula (VI),

the invention provides an N crystal form of a compound of formula (VI), which is characterized in that an X-ray powder diffraction pattern of the N crystal form has characteristic diffraction peaks at the following 2 theta angles: 11.439 +/-0.200 degrees, 18.363 +/-0.200 degrees and 28.859 +/-0.200 degrees.

In some embodiments of the invention, the above N crystalline form has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 11.439 +/-0.200 degrees, 18.363 +/-0.200 degrees, 20.062 +/-0.200 degrees, 22.657 +/-0.200 degrees and 28.859 +/-0.200 degrees.

In some embodiments of the invention, the above N crystalline form has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 8.581 +/-0.200 degrees, 11.439 +/-0.200 degrees, 18.363 +/-0.200 degrees, 20.062 +/-0.200 degrees, 22.657 +/-0.200 degrees, 23.664 +/-0.200 degrees, 25.356 +/-0.200 degrees and 28.859 +/-0.200 degrees.

In some embodiments of the invention, the above N crystalline form has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.697 °,8.581 °,8.801 °,11.439 °,12.051 °,12.568 °,13.226 °,14.357 °,14.846 °,15.655 °,16.120 °,17.223 °,17.880 °,18.363 °,18.914 °,19.236 °,20.062 °,20.397 °,21.454 °,22.657 °,22.991 °,23.664 °,24.391 °,24.844 °,25.356 °,26.003 °,26.573 °,26.956 °,27.309 °, 28.914 °,28.859 °,29.089 °,29.935 °,31.553 °,31.847 °,32.174 °,32.715 °,34.782 °,38.569 °.

In some embodiments of the invention, the XRPD pattern of the crystalline form N is substantially as shown in figure 18.

In some embodiments of the invention, XRPD pattern analysis data for the above form N is shown in table 14:

TABLE 14 XRPD pattern analysis data for crystalline form N of compound of formula (VI)

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The invention also provides compounds of formula (VII),

wherein p is selected from 0 to 3, and can be 0, 1/2, 2/3, 1, 1.5, 2, 2.5, 2.7 and 3.

The invention provides an O crystal form of a compound of a formula (VII), which is characterized in that an X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 9.485 +/-0.200 degrees, 11.273 +/-0.200 degrees, 17.536 +/-0.200 degrees.

In some embodiments of the invention, the above form O has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 9.485 +/-0.200 degrees, 11.273 +/-0.200 degrees, 12.495 +/-0.200 degrees, 17.536 +/-0.200 degrees and 18.874 +/-0.200 degrees.

In some embodiments of the invention, the above form O has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 9.485 plus or minus 0.200 degrees, 11.273 plus or minus 0.200 degrees, 12.495 plus or minus 0.200 degrees, 15.005 plus or minus 0.200 degrees, 17.536 plus or minus 0.200 degrees, 18.874 plus or minus 0.200 degrees, 19.568 plus or minus 0.200 degrees and 20.291 plus or minus 0.200 degrees.

In some embodiments of the invention, the above form O has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 4.859 °,7.487 °,9.485 °,10.000 °,11.273 °,12.495 °,12.842 °,14.649 °,15.005 °,16.766 °,17.536 °,18.874 °,19.568 °,20.082 °,20.291 °,21.189 °,22.679 °,23.508 °,25.140 °,25.788 °,28.081 °,29.067 °,29.739 °,31.639 °,35.581 °.

In some embodiments of the invention, the form O above has an XRPD pattern substantially as shown in figure 19.

In some embodiments of the invention, XRPD pattern analysis data for the above form O is shown in table 15:

TABLE 15 XRPD pattern analysis data for form O of compound of formula (VII)

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The invention provides a crystal form P of a compound of formula (VII), which is characterized in that an X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 12.481 plus or minus 0.200 degrees, 14.965 plus or minus 0.200 degrees and 17.480 plus or minus 0.200 degrees.

In some embodiments of the invention, the above form P has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 9.998 +/-0.200 degrees, 12.481 +/-0.200 degrees, 14.965 +/-0.200 degrees, 17.480 +/-0.200 degrees and 19.969 +/-0.200 degrees.

In some embodiments of the invention, the above form P has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 5.007 °,7.512 °,9.604 °,9.998 °,12.481 °,14.965 °,17.480 °,18.908 °,19.969 °,20.933 °,25.629 °,27.587 °,35.375 °.

In some embodiments of the invention, the form P is substantially as shown in figure 20 with an XRPD pattern.

In some embodiments of the invention, the XRPD pattern analysis data for form P above is shown in table 16:

table 16 XRPD pattern analysis data for form P of compound of formula (VII)

The invention also provides a compound of formula (VIII),

the invention provides a crystal form Q of a compound of formula (VIII), which is characterized in that an X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2 theta angles: 6.123 +/-0.200 degrees, 9.130 +/-0.200 degrees and 12.123 +/-0.200 degrees.

In some embodiments of the invention, the above form Q has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.123 +/-0.200 degrees, 9.130 +/-0.200 degrees, 12.123 +/-0.200 degrees, 20.095 +/-0.200 degrees and 22.942 +/-0.200 degrees.

In some embodiments of the invention, the crystalline form Q has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.123 +/-0.200 degrees, 9.130 +/-0.200 degrees, 12.123 +/-0.200 degrees, 15.071 +/-0.200 degrees, 18.151 +/-0.200 degrees, 20.095 +/-0.200 degrees, 22.045 +/-0.200 degrees and 22.942 +/-0.200 degrees.

In some embodiments of the invention, the above form Q has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.123 °,7.677 °,9.130 °,10.013 °,11.598 °,12.123 °,14.770 °,15.071 °,15.986 °,16.493 °,16.692 °,17.365 °,18.151 °,18.915 °,20.095 °,20.569 °,21.147 °,22.045 °,22.942 °,24.106 °,24.617 °,26.108 °,27.014 °,27.822 °,28.433 °,29.464 °,30.256 °,30.863 °,31.820 °,33.446 °,34.822 °,36.389 °,37.646 °,37.803 °.

In some embodiments of the invention, the form Q above has an XRPD pattern substantially as shown in figure 21.

In some embodiments of the invention, the XRPD pattern analysis data for form Q above is shown in table 17:

TABLE 17 XRPD pattern analysis data for form Q of compound of formula (VIII)

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The invention also provides compounds of formula (I),

wherein s is selected from 0 to 3, and may be, for example, 0, 1/2, 2/3, 1, 1.5, 2, 2.5, 2.7 or 3.

In some embodiments of the invention, s is selected from 0, 1, 2 and 3.

In some embodiments of the invention, the compound of formula (I) has the structure,

the invention provides a crystal form R of a compound shown as a formula (I), which is characterized in that an X-ray powder diffraction pattern of the crystal form R has characteristic diffraction peaks at the following 2 theta angles: 7.933 +/-0.200 degrees, 15.900 +/-0.200 degrees, 23.970 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the form R has characteristic diffraction peaks at the following 2 Θ angles: 7.933 +/-0.200 degrees, 11.906 +/-0.200 degrees, 15.900 +/-0.200 degrees, 19.923 +/-0.200 degrees and 23.970 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the form R has characteristic diffraction peaks at the following 2 Θ angles: 3.935 +/-0.200 degrees, 7.933 +/-0.200 degrees, 11.906 +/-0.200 degrees, 15.900 +/-0.200 degrees, 19.923 +/-0.200 degrees and 23.970 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the form R has characteristic diffraction peaks at the following 2 Θ angles: 3.935 °,7.933 °,11.906 °,15.900 °,17.731 °,19.923 °,21.294 °,23.503 °,23.970 °,25.040 °,26.811 °,28.041 °,28.913 °,31.180 °,32.172 °,34.091 °,38.072 °.

In some embodiments of the invention, the form R above has an XRPD pattern substantially as shown in figure 22.

In some embodiments of the invention, the XRPD pattern analysis data for form R above is shown in table 18:

TABLE 18 XRPD pattern analysis data for form R of compound of formula (I)

The invention provides a crystal form S of a compound of formula (I), which is characterized in that an X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 20.032 +/-0.200 degrees, 21.239 +/-0.200 degrees, 23.474 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above S form has characteristic diffraction peaks at the following 2 Θ angles: 15.569 +/-0.200 degrees, 17.781 +/-0.200 degrees, 20.032 +/-0.200 degrees, 21.239 +/-0.200 degrees and 23.474 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above form S has characteristic diffraction peaks at the following 2 Θ angles: 14.527 +/-0.200 degrees, 15.569 +/-0.200 degrees, 17.781 +/-0.200 degrees, 20.032 +/-0.200 degrees, 21.239 +/-0.200 degrees, 23.474 +/-0.200 degrees, 24.275 +/-0.200 degrees and 26.863 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above S form has characteristic diffraction peaks at the following 2 Θ angles: 3.871 °,7.901 °,9.387 °,9.859 °,11.461 °,14.527 °,15.569 °,15.906 °,16.743 °,17.781 °,18.461 °,20.032 °,20.378 °,21.239 °,23.474 °,24.275 °,25.367 °,26.863 °,27.063 °,28.954 °,31.135 °,34.181 °.

In some embodiments of the invention, the form S has an XRPD pattern substantially as shown in figure 23.

In some embodiments of the invention, XRPD pattern analysis data for the above form S is shown in table 19:

TABLE 19 XRPD pattern analysis data for form S of compound of formula (I)

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The invention provides a T crystal form of a compound shown as a formula (I-1), which is characterized in that an X-ray powder diffraction pattern of the T crystal form has characteristic diffraction peaks at the following 2 theta angles: 6.347 + -0.200 deg., 11.735 + -0.200 deg., 18.221 + -0.200 deg..

In some embodiments of the invention, the crystalline form T has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.347 +/-0.200 degrees, 11.012 +/-0.200 degrees, 11.735 +/-0.200 degrees, 18.221 +/-0.200 degrees and 20.525 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above form T has characteristic diffraction peaks at the following 2 Θ angles: 6.347 +/-0.200 degrees, 11.012 +/-0.200 degrees, 11.735 +/-0.200 degrees, 15.525 +/-0.200 degrees, 17.028 +/-0.200 degrees, 18.221 +/-0.200 degrees, 20.525 +/-0.200 degrees and 25.872 +/-0.200 degrees.

In some embodiments of the invention, the X-ray powder diffraction pattern of the above form T has characteristic diffraction peaks at the following 2 Θ angles: 6.347 °,9.315 °,10.351 °,11.012 °,11.735 °,12.780 °,14.017 °,15.525 °,16.475 °,17.028 °,18.221 °,19.285 °,20.213 °,20.525 °,22.738 °,23.383 °,23.924 °,25.039 °,25.872 °,26.855 °,31.419 °.

In some embodiments of the invention, the form T above has an XRPD pattern substantially as shown in figure 24.

In some embodiments of the invention, XRPD pattern analysis data for the above form T is shown in table 20:

TABLE 20 XRPD pattern analysis data for compound of formula (I-1) form T

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The invention provides a U crystal form of a compound shown as a formula (I-1), which is characterized in that an X-ray powder diffraction pattern of the U crystal form has characteristic diffraction peaks at the following 2 theta angles: 4.486 +/-0.200 degrees, 9.021 +/-0.200 degrees and 27.215 +/-0.200 degrees.

In some embodiments of the invention, the above form U has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 4.486 +/-0.200 degrees, 9.021 +/-0.200 degrees, 14.894 +/-0.200 degrees, 23.876 +/-0.200 degrees and 27.215 +/-0.200 degrees.

In some embodiments of the invention, the above form U has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 4.486 +/-0.200 degrees, 9.021 +/-0.200 degrees, 14.894 +/-0.200 degrees, 18.620 +/-0.200 degrees, 19.150 +/-0.200 degrees, 22.042 +/-0.200 degrees, 23.876 +/-0.200 degrees and 27.215 +/-0.200 degrees.

In some embodiments of the invention, the crystalline form U has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 4.486 °,9.021 °,10.970 °,13.600 °,14.894 °,15.853 °,18.076 °,18.620 °,19.150 °,22.042 °,23.876 °,26.295 °,27.215 °,28.304 °,30.674 °,31.304 °.

In some embodiments of the invention, the crystalline form U as described above has an XRPD pattern substantially as shown in figure 25.

In some embodiments of the invention, XRPD pattern analysis data for the above form U is shown in table 21:

TABLE 21 XRPD pattern analysis data for form U of compound of formula (I-1)

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The invention provides a crystal form V of a compound shown as a formula (I), which is characterized in that an X-ray powder diffraction pattern of the crystal form V has characteristic diffraction peaks at the following 2 theta angles: 3.729 +/-0.200 degrees, 11.208 +/-0.200 degrees and 23.480 +/-0.200 degrees.

In some embodiments of the invention, the crystalline form V has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 3.729 +/-0.200 degrees, 11.208 +/-0.200 degrees, 15.943 +/-0.200 degrees, 21.259 +/-0.200 degrees and 23.480 +/-0.200 degrees.

In some embodiments of the invention, the crystalline form V has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 3.729 +/-0.200 degrees, 11.208 +/-0.200 degrees, 15.943 +/-0.200 degrees, 18.814 +/-0.200 degrees, 19.613 +/-0.200 degrees, 20.013 +/-0.200 degrees, 21.259 +/-0.200 degrees and 23.480 +/-0.200 degrees.

In some embodiments of the invention, the crystalline form V has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 3.729 °,7.556 °,7.930 °,11.208 °,14.132 °,14.587 °,15.943 °,17.855 °,18.814 °,19.613 °,20.013 °,21.259 °,21.476 °,21.966 °,23.271 °,23.480 °,24.340 °,25.142 °,25.409 °,26.267 °,26.849 °,27.469 °.

In some embodiments of the invention, the form V above has an XRPD pattern substantially as shown in figure 26.

In some embodiments of the invention, XRPD pattern analysis data for the above form V is shown in table 22:

TABLE 22 XRPD pattern analysis data for crystalline form V of compound of formula (I)

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The invention also provides application of the compound or the crystal forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U and V in preparation of medicines for treating diabetes, losing weight and NASH.

Definitions and explanations

As used herein, the following terms and phrases are intended to have the following meanings unless otherwise indicated. A particular phrase or term should not be considered as ambiguous or unclear without special definition, but rather construed in a generic sense. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

The intermediate compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof well known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present invention.

The chemical reactions of the embodiments of the present invention are carried out in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

The compounds of the present invention may be structurally confirmed by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of the compound, the absolute configuration may be confirmed by means of conventional techniques in the art. For example, in the single crystal X-ray diffraction method (SXRD), diffraction intensity data of the cultured single crystal is collected by a Bruker D8 feature diffractometer, a light source is CuK α radiation, and a scanning mode:

after scanning and collecting relevant data, the crystal structure is further analyzed by a direct method (Shelxs 97), so that the absolute configuration can be confirmed.

The present invention will be specifically described below by way of examples, which are not intended to limit the present invention in any way.

All solvents used in the present invention are commercially available and can be used without further purification.

The solvent used in the present invention can be obtained commercially.

The invention employs the following abbreviations: aq represents water; eq represents equivalent, equivalent; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; MEK represents butanone; etOH stands for ethanol; meOH represents methanol; IPA stands for isopropanol; MTBE represents methyl tert-butyl ether; THF represents tetrahydrofuran; pd (dppf) Cl ₂ Represents [1, 1-bis (diphenylphosphino) ferrocene]Palladium dichloride; pd (OH) ₂ Represents palladium hydroxide, liAlH ₄ Represents lithium aluminum hydride; tris stands for tromethamine.

The compounds are named according to the conventional nomenclature in the art or used

The software names, and the commercial compounds are under the supplier catalog name.

Technical effects

The compound has stable crystal form, small influence by heat and humidity, good in-vivo administration drug effect and wide patent drug prospect; the compounds of formula (I) exhibit superior agonistic activity at the GLP-1 receptor.

The invention relates to an X-ray powder diffraction (XRPD) method

1. The instrument model is as follows: x-ray diffractometer model X' Pert3 from PANALYTICAL (Pasacaceae)

The test method comprises the following steps: approximately 20mg of sample was used for XRPD detection.

The detailed parameters are as follows:

x-ray diffraction patterns were obtained from a D2 Phaser type acquisition with a brook instrument, with the instrument parameters as follows.

Differential thermal analysis (DSC) method of the present invention

The instrument model is as follows: TA 2500 differential scanning calorimeter

The parameters and test methods were as follows:

parameter(s)	Set value
		Method	Linear temperature rise
Sample plate	Aluminium pan, gland/non-gland
		Temperature range	25-set end point temperature
Scanning Rate (. Degree.C./min)	10
		Protective gas	Nitrogen gas

The present invention is a Thermal Gravimetric Analysis (TGA) method

The instrument model is as follows: TA 5500 thermogravimetric analyzer

The parameters and test methods were as follows:

the invention relates to a Dynamic Vapor adsorption analysis (DVS) method

Dynamic water sorption (DVS) curves were collected on a DVS Intrasic plus by SMS (Surface Measurement Systems). At a relative humidity of 25 deg.C, lithium chloride (LiCl), magnesium nitrate [ Mg (NO) ₃ ) ₂ ]And deliquescence point correction of potassium chloride (KCl).

The test parameters were as follows:

the hygroscopicity evaluation was classified as follows:

classification of hygroscopicity	ΔW％
		Deliquescence	Absorb sufficient water to form liquid
Is very hygroscopic	ΔW％≥15％
		Has moisture absorption	15％>ΔW％≥2％
Slightly hygroscopic	2％>ΔW％≥0.2％
		No or almost no hygroscopicity	ΔW％<0.2％

Note: Δ W% represents the moisture absorption weight gain of the test article at 25. + -. 1 ℃ and 80. + -. 2% RH.

Drawings

FIG. 1 is an XRPD spectrum of Cu-Ka radiation of a crystal form A of compound of formula (II-1);

FIG. 2 is a DSC of crystalline form A of compound of formula (II-1);

FIG. 3 is a TGA spectrum of crystalline form A of compound of formula (II-1);

FIG. 4 is an XRPD spectrum of Cu-Ka radiation of form B of compound of formula (II);

FIG. 5 is an XRPD spectrum of Cu-Ka radiation of form C of compound of formula (II);

FIG. 6 is an XRPD spectrum of Cu-Ka radiation of form D of compound of formula (II);

FIG. 7 is an XRPD pattern of Cu-Ka radiation of crystalline form E of compound of formula (II);

FIG. 8 is a DSC of form E of compound of formula (II);

FIG. 9 is a TGA profile of Compound E crystalline form of formula (II);

FIG. 10 is an XRPD spectrum of Cu-Ka radiation of crystalline form F of compound of formula (II);

FIG. 11 is an XRPD pattern of Cu-Ka radiation of crystalline form G of compound of formula (II);

FIG. 12 is an XRPD spectrum of Cu-Ka radiation of form H of compound of formula (II);

FIG. 13 is an XRPD pattern of Cu-Ka radiation of crystalline form I of compound of formula (II);

FIG. 14 is an XRPD spectrum of Cu-Ka radiation of crystalline form J of compound of formula (III);

FIG. 15 is an XRPD spectrum of Cu-Ka radiation of crystalline form K of compound of formula (IV-1);

FIG. 16 is an XRPD pattern of Cu-Ka radiation of crystalline form L of compound of formula (IV);

FIG. 17 is an XRPD spectrum of Cu-Ka radiation of form M of compound of formula (V);

FIG. 18 is an XRPD spectrum of Cu-Ka radiation of crystalline form N of compound of formula (VI);

FIG. 19 is an XRPD spectrum of Cu-Ka radiation of form O of compound of formula (VII);

FIG. 20 is an XRPD spectrum of Cu-Ka radiation of form P of compound of formula (VII);

FIG. 21 is an XRPD spectrum of Cu-Ka radiation of crystalline form Q of compound of formula (VII);

FIG. 22 is an XRPD pattern of Cu-Ka radiation of form R of compound of formula (I);

FIG. 23 is an XRPD pattern of Cu-Ka radiation of form S of compound of formula (I);

FIG. 24 is an XRPD spectrum of Cu-Ka radiation of form T of compound of formula (I-1);

FIG. 25 is an XRPD pattern of Cu-Ka radiation of crystalline form U of compound of formula (I-1);

FIG. 26 is an XRPD pattern of Cu-Ka radiation of crystalline form U of compound of formula (I);

FIG. 27 is a DVS spectrum of crystalline form A of compound of formula (II-1);

figure 28 is a DVS spectrum of crystalline form E of compound of formula (II);

figure 29 is a DVS spectrum of crystalline form Q of compound of formula (VIII).

Detailed Description

For better understanding of the present invention, the following description is given with reference to specific examples, but the present invention is not limited to the specific embodiments.

Example 1: synthesis of Compounds of formula (I)

Step 1: synthesis of Compound B-1-3

Adding B-1-1 (1.00g, 6.23mmol and 1eq) into a reaction bottle containing THF (40 mL), adding NaH (375mg, 9.38mmol,60% content and 1.51 eq) at 0 ℃ under the protection of nitrogen, heating to 22 ℃, stirring for 1 hour, adding B-1-2 (1.5g, 6.33mmol and 1.02eq) and heating to 60 ℃, and stirring for 16 hours. The reaction was quenched by addition of 20mL of water, extracted with DCM (20ml × 3), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product is separated and purified by column chromatography (petroleum ether: ethyl acetate = 1) to obtain B-1-3.LCMS m/z =317.8[ m + H ]] ⁺ 。

Step 2: synthesis of Compound B-1-5

B-1-3 (1.50g, 4.74mmol, 1eq), B-1-4 (1.50g, 4.85mmol, 1.02eq), sodium carbonate (1.50g, 14.15mmol, 2.99eq), dioxane (30 mL), water (6 mL) were charged into a reaction flask, and Pd (dppf) Cl was added under nitrogen atmosphere ₂ (0.17g, 232.33. Mu. Mol,0.05 eq) and the reaction was stirred at 100 ℃ for 3 hours. Concentrating the reaction solution to obtain crude product, adding water (50 mL), extracting with ethyl acetate (50mL × 3), mixing organic phases, washing the organic phase with saturated aqueous sodium chloride solution (50 mL), drying over anhydrous sodium sulfate,filtering, and concentrating the filtrate to obtain crude product. The crude product is separated and purified by column chromatography (petroleum ether: ethyl acetate = 1.LCMS m/z =419.2[ m + H ]] ⁺ 。

And step 3: synthesis of Compound B-1

B-1-5 (1.80g, 4.30mmol, 1eq), anhydrous DCM (30 mL) was added to the reaction flask, trifluoroacetic acid (7.70g, 67.53mmol,5.0mL, 15.72eq) was added and the reaction stirred at 20 ℃ for 12 hours. To the reaction solution was added sodium carbonate solution (30 mL), sodium carbonate solid was added to adjust the pH to about 9-10, extracted with ethyl acetate (30ml × 3), the organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was isolated and purified by column chromatography (DCM: meOH = 1). LCMS m/z =319.1[ m + H ]] ⁺ 。

And 4, step 4: synthesis of Compound B-2-2

Compound B-2-1 (12g, 67.33mmol, 1eq) was dissolved in THF (120 mL), argon was replaced, and Pd (OH) was added ₂ (6.00g, 4.27mmol,10% content, 6.35e-2 eq), hydrogen was passed through under a pressure of 50psi and stirred at 45 ℃ for 24 hours. The reaction solution was filtered through celite and rinsed with anhydrous THF. The THF solution of B-2-2 was obtained and directly subjected to the next reaction without any post-treatment. ¹ H NMR(400MHz,CDCl ₃ )δppm 7.10-7.16(m,2H),7.03-7.07(m,2H),4.75-4.83(m,1H),4.52-4.61(m,1H),4.39-4.46(m,1H)。

And 5: synthesis of Compound B-2

Compound B-2-2 (2g, 22.70mmol, 1eq) and TEA (13.78g, 136.20mmol,18.96mL,6 eq) were charged into a reaction flask, and methanesulfonic anhydride (11.86g, 68.10mmol,2.64mL, 3eq) was added in portions at 0 ℃ after purging nitrogen, followed by heating to 25 ℃ for 24 hours. The reaction was quenched by pouring into water (125 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 ℃ with a water pump to give the crude product. By column chromatography (P)E, EA =1:0 to 1, gradient elution) separation and purification. B-2 is obtained. ¹ H NMR(400MHz,CDCl ₃ )δppm 4.99-5.05(m,1H),4.64-4.71(m,1H),4.57(dt,J＝9.10,6.08Hz,1H),4.36(d,J＝3.88Hz,2H),3.10(s,3H),2.70-2.81(m,1H),2.58-2.68(m,1H)。

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Step 6: synthesis of Compound 1-2

Compound 1-1 (23g, 164.12mmol, 1eq) and DMF (115 mL) were charged in a reaction flask, nitrogen was replaced, the temperature was lowered to 0 ℃ and NaH (9.85g, 246.18mmol,60% content, 1.5 eq) was added, nitrogen was replaced again, 2- (trimethylsilyl) ethoxymethyl chloride (41.04g, 246.18mmol,43.57mL,1.5 eq) was added dropwise, and the temperature was raised to 25 ℃ after completion of the addition and reacted for 12 hours. The reaction was quenched with ice water (500 mL), extracted with ethyl acetate (200ml x 3), the organic phases were combined, washed with saturated brine (200ml x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 ℃ with a water pump to give the crude product. The crude product was isolated and purified by column chromatography (PE: EA =1 to 0 to 1, gradient elution) to give 1-2. ¹ H NMR(400MHz,CDCl ₃ )δppm 7.24(d,J＝0.63Hz,1H),7.17(s,1H),5.76(s,2H),4.39(q,J＝7.13Hz,2H),3.49-3.56(m,2H),1.40(t,J＝7.13Hz,3H),0.86-0.93(m,2H),-0.07--0.04(m,9H)。

And 7: synthesis of Compounds 1-3

THF (1000 mL) was added to the reaction flask and LiAlH was added in portions ₄ (6.04g, 159.21mmol, 1.5eq), replacement of nitrogen, cooling to 0 ℃, stirring for 15 minutes, addition of compound 1-2 (28.7g, 106.14mmol, 1eq) at 0 ℃, and subsequent warming to 25 ℃ for 0.5 hours. The reaction solution was cooled to 0 ℃, then 6mL of water, 6mL of 15% sodium hydroxide and 18mL of water were sequentially added, the temperature was raised to 25 ℃ and stirred for 15 minutes, then anhydrous magnesium sulfate was added and stirred for 15 minutes, and filtration was carried out. The filtrate was collected, washed with saturated brine (500 mL) and anhydrous sulfurDrying sodium salt, filtering, and concentrating the filtrate at 45 deg.C under reduced pressure with water pump to obtain compound 1-3. ¹ H NMR(400MHz,CDCl ₃ )δppm 6.98(d,J＝1.13Hz,1H),6.93(d,J＝1.13Hz,1H),5.37(s,2H),4.72(s,2H),3.52(dd,J＝8.76,7.75Hz,2H),0.89-0.95(m,2H),-0.02--0.01(m,9H)。

And step 8: synthesis of Compounds 1-4

Compounds 1 to 3 (18.81g, 82.37mmol, 1eq), t-butyldiphenylchlorosilane (27.17g, 98.84mmol,25.39mL, 1.2eq), imidazole (14.02g, 205.92mmol, 2.5eq), and DMF (188 mL) were charged into a reaction flask, nitrogen was replaced, and the reaction was carried out at 25 ℃ for 16 hours. The reaction solution was quenched by pouring water (1000 mL), extracted with ethyl acetate (200ml x 3), the organic phases were combined, washed with saturated brine (200ml x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 ℃ with a water pump to give a crude product. The crude product was isolated and purified by column chromatography (PE: EA =1 to 0 to 1, gradient elution) to give 1-4. ¹ H NMR(400MHz,CDCl ₃ )δppm 7.66-7.72(m,4H),7.37-7.46(m,6H),6.96-7.02(m,2H),5.41(s,2H),4.84(s,2H),3.41-3.48(m,2H),1.06(s,9H),0.85-0.91(m,2H),-0.03(s,9H)。

And step 9: synthesis of Compounds 1-5

Compound 1-4 (22g, 47.13mmol, 1eq) and THF (440 mL) were charged to a reaction flask, N-bromosuccinimide (25.17g, 141.40mmol, 44.18. Mu.L, 3 eq) was added in portions at 0 ℃ after nitrogen gas was purged, and then the temperature was raised to 25 ℃ for 12 hours. The reaction mixture was quenched with water (440 mL), extracted with ethyl acetate (2200 mL × 2), the organic phases were combined, washed with saturated brine (2200 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 30 ℃ using a water pump to give a crude product. The crude product was isolated and purified by column chromatography (PE: EA =1 to 2, gradient elution) to give 1-5. ¹ H NMR(400MHz,CDCl ₃ )δppm 7.64-7.67(m,4H),7.37-7.48(m,6H),5.44(s,2H),4.80(s,2H),3.45-3.51(m,2H),1.07(s,9H),0.85-0.90(m,2H),-0.02(s,9H)。

Step 10: synthesis of Compounds 1-6

The compound 1-5 (6 g,9.61mmol, 1eq) and THF (60 mL) were charged in a reaction flask, nitrogen was replaced, the temperature was lowered to-40 deg.C, then i-PrMgCl-LiCl (1.3M, 8.13mL, 1.1eq) was added dropwise, stirring was carried out for 1.5 hours, and then DMF (61.62g, 843.09mm, DMF) was added dropwiseol,64.86mL, 87.76eq), warmed to 25 ℃ and stirred for 30 minutes. The reaction was quenched with water (120 mL), extracted with ethyl acetate (50ml × 2), the organic phases combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure at 45 ℃ with a water pump to give the crude product. The crude product was isolated and purified by column chromatography (PE: EA =1 to 10, gradient elution) to give 1-6. ¹ H NMR(400MHz,CDCl ₃ )δppm9.76(s,1H),7.64-7.68(m,5H),7.38-7.42(m,5H),5.85(s,2H),4.86(s,2H),3.49-3.54(m,2H),1.07(s,9H),0.84-0.88(m,2H),-0.03(s,9H)。

Step 11: synthesis of Compounds 1-8

Compounds 1 to 6 (1.23g, 2.14mmol, 1eq) were dissolved in EtOH (61.5 mL), sodium ethoxide (2.19g, 6.43mmol,20% content, 3 eq), 1 to 7 (273.10mg, 2.57mmol, 233.42. Mu.L, 1.2 eq) were added, stirred at 20 ℃ for 2 hours, then warmed to 80 ℃ and stirred for 12 hours. The reaction was quenched with water (50 mL), extracted 2 times with ethyl acetate (25 mL), the organic phases combined, washed with saturated brine (50 mL), filtered, and the filtrate was pumped to 45 ℃ and concentrated under reduced pressure and spin-dried to give the crude product. The crude product was isolated and purified by column chromatography (PE: EA =1 to 10, gradient elution) to afford compounds 1-8. ¹ H NMR(400MHz,CDCl ₃ )δppm 7.72(s,1H),5.54(s,2H),4.91(s,2H),4.39(q,J＝7.13Hz,2H),3.55-3.61(m,2H),2.30-2.64(m,1H),1.40(t,J＝7.13Hz,3H),0.91-0.96(m,2H),-0.02(s,9H)。

Step 12: synthesis of Compounds 1-9

To a reaction flask were added compounds 1 to 8 (120mg, 336.59. Mu. Mol,1 eq), triethylamine (102.18mg, 1.01mmol, 140.55. Mu.L, 3 eq) and DCM (2 mL), nitrogen gas was purged and methanesulfonyl chloride (57.84mg, 504.89. Mu. Mol, 39.08. Mu.L, 1.5 eq) was added in portions at 0 ℃ followed by warming to 25 ℃ for 12 hours. The reaction solution is directly decompressed and concentrated to obtain a crude product. Purification by thin layer chromatography silica gel plate (DCM: meOH = 20) separation afforded compounds 1-9. ¹ H NMR(400MHz,CDCl ₃ )δppm 7.72(s,1H),5.57(s,2H),4.85(s,2H),4.39(q,J＝7.13Hz,2H),3.56-3.61(m,2H),1.40(t,J＝7.13Hz,3H),0.92-0.97(m,2H),-0.02(s,9H)。

Step 13: synthesis of Compounds 1-10

1-9 (0.16g, 426.72. Mu. Were added to the reaction flask in sequencemol,1 eq), B-1 (0.30g, 941.11. Mu. Mol,2.21 eq), potassium carbonate (0.10g, 723.56. Mu. Mol,1.70 eq), acetonitrile (10 mL), the reaction system was stirred at 60 ℃ for 10 hours. The reaction was concentrated to give a crude product, water (10 mL) was added, extraction was performed with ethyl acetate (10 mL × 3), the organic phases were combined, the organic phase was washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product is separated and purified by column chromatography (petroleum ether: ethyl acetate =1: 0-5) to obtain 1-10.LCMS m/z =657.3[ m + H ]] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δppm 7.74(s,1H),7.55(t,J＝7.91Hz,1H),7.43(t,J＝8.03Hz,1H),7.08-7.17(m,2H),6.94(d,J＝7.28Hz,1H),6.72(br s,1H),6.66(d,J＝8.28Hz,1H),5.66(s,2H),5.43(s,2H),4.38(q,J＝7.03Hz,2H),3.95(s,2H),3.52-3.57(m,2H),3.29(br s,2H),2.79-2.85(m,2H),2.61(br s,2H),1.40(t,J＝7.03Hz,3H),0.89-0.94(m,2H),-0.10--0.03(m,9H)。

Step 14: synthesis of Compounds 1-11

To the reaction flask were added 1-10 (0.30g, 456.43. Mu. Mol,1 eq) and anhydrous DCM (5.0 mL) in that order, and trifluoroacetic acid (1.54g, 13.51mmol,1.0mL, 29.59eq) was added and the reaction stirred at 40 ℃ for 5 hours. Adding sodium carbonate solution (10 mL), adding sodium carbonate solid to adjust pH to about 9-10, extracting with ethyl acetate (10 mL × 3), combining organic phases, washing the organic phase with saturated aqueous sodium chloride solution (10 mL), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain crude product. The crude product is separated and purified by column chromatography (petroleum ether: ethyl acetate = 10) to obtain 1-11.LCMS m/z =527.2[ M + H ]] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )δppm 10.08(br s,1H),7.68(br s,1H),7.57(t,J＝7.78Hz,1H),7.43(t,J＝8.16Hz,1H),7.09-7.17(m,2H),6.96(d,J＝7.53Hz,1H),6.73(br s,1H),6.69(d,J＝8.28Hz,1H),5.44(s,2H),4.37(q,J＝7.11Hz,2H),3.96(s,2H),3.35(br d,J＝3.01Hz,2H),2.83-2.91(m,2H),2.68(br s,2H),1.39(t,J＝7.15Hz,3H)。

Step 15: synthesis of Compounds 1-12 and 1-13

1 to 11 (0.20g, 379.50. Mu. Mol,1 eq), B-2 (0.35g, 2.11mmol, 5.55eq), potassium carbonate (0.40g, 1.23mmol, 3.23eq), and acetonitrile (5 mL) were sequentially added to a reaction flask, and the reaction was stirred at 80 ℃ for 10 hours. Will be reversedThe reaction solution was concentrated to give a crude product, water (10 mL) was added, extraction was performed with ethyl acetate (10 mL × 3), the organic phases were combined, the organic phase was washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product. The crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate =1: 0-1) to give a mixture of 1-12 and 1-13. LCMS (retention time: 3.508): m/z =597.1[ M ] +H] ⁺ (ii) a LCMS (retention time: 3.566): m/z =597.3[ m ] +H] ⁺ . Step 16: synthesis of Compounds of formula (I)

To a reaction flask were added a mixture of 1-12 and 1-13 (90mg, 150.73. Mu. Mol,1 eq), water (0.4 mL), acetonitrile (2 mL), 1,5, 7-triazabicyclo (4.4.0) dec-5-ene (50mg, 359.20. Mu. Mol,2.38 eq) in this order, and the reaction was stirred at 20 ℃ for 10 hours. And concentrating the reaction solution to obtain a crude product. The crude product was isolated and purified by preparative TLC (DCM: meOH = 10). The mixture was subjected to supercritical fluid chromatography (column DAICEL CHIRALPAK IG (250mm. About.30mm, 10 μm); mobile phase: [0.1% ]NH ₃ H ₂ O MeOH]；CO ₂ 55% -55%, min) to obtain the compound of formula (I) (retention time: 6.815 min).

Detection method (chromatographic column: chiralpak IG-3)

4.6mm I.D.,3 μm, mobile phase A: CO ₂ And B, methanol (0.05 percent diethylamine), wherein the methanol (0.05 percent diethylamine) is eluted in an isocratic manner at the flow rate of 4mL/min, the column temperature is 35 ℃, and the back pressure is 1500 psi. LCMS m/z =569.2[ M + H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δppm 7.68(t,J＝7.91Hz,1H),7.55(t,J＝8.16Hz,1H),7.40-7.50(m,2H),7.30(dd,J＝8.28,1.76Hz,1H),7.08(d,J＝7.53Hz,1H),6.68-6.77(m,2H),5.39(s,2H),4.97-5.08(m,1H),4.52-4.60(m,1H),4.40-4.50(m,2H),4.28-4.38(m,1H),3.74-3.92(m,2H),3.18(br s,2H),2.68(br d,J＝5.52Hz,2H),2.58-2.66(m,1H),2.32-2.38(m,1H)； ¹ H NMR(400MHz,CD ₃ OD)δppm7.64(s,1H),7.62(t,J＝7.91Hz,1H),7.48(t,J＝8.03Hz,1H),7.16-7.24(m,2H),7.05(d,J＝7.53Hz,1H),6.71(br s,1H),6.68(d,J＝8.03Hz,1H),5.42(s,2H),5.19(br d,J＝4.27Hz,2H),4.36-4.45(m,1H),3.93-4.05(m,2H),2.82-2.90(m,2H),2.68-2.76(m,1H),2.63(br s,2H),2.48(br d,J＝8.78Hz,1H)。

Identification of C by two-dimensional Nuclear magnetic NOE ₈ -H and C ₁₀ And (4) related to H, and the product structure is correct.

Example 2: preparation of the crystalline form

Preparation of crystal form a:

tromethamine (1.31g, 10.8mmol, 1.02eq) and 30mL of methanol were sequentially added to a reaction flask, and the system was stirred and dissolved at 50 ℃. The temperature is reduced to 25 ℃, the compound (6 g,10.54mmol, 1eq) of the formula (I) is added, and the system is dissolved clearly. 90mL of methyl t-butyl ether was added and stirred at 25 ℃ for 16 hours. The filter cake was rinsed 3 times with 12mL of a mixed solvent of methanol and methyl tert-butyl ether =1, and the filter cake was transferred to 50 ℃ for vacuum drying for 16 hours. To obtain the compound A crystal form of the formula (II-1). ¹ H NMR(400MHz,CD ₃ OD)δppm 7.57-7.68(m,2H)7.50(t,J＝7.91Hz,1H)7.16-7.28(m,2H)7.06(d,J＝7.53Hz,1H)6.63-6.79(m,2H)5.44(s,2H)5.15-5.28(m,1H)4.55-4.80(m,3H)4.44(dt,J＝9.29,6.02Hz,1H)3.89-4.04(m,2H)3.68(s,6H)3.26(br s,2H)2.68-2.86(m,3H)2.63(br s,2H)2.43-2.55(m,1H)。

Preparation of crystal form B:

weigh about 15mg of Compound A form of formula (II-1) into an HPLC glass vial, add 0.5mL of H each ₂ And O, placing the obtained turbid solution at room temperature, magnetically stirring (1000 rpm) for about 4 days, and centrifuging to collect solid to obtain the compound B crystal form of the formula (II). The sample was allowed to dry to room temperature overnight before transferring to form E.

Preparation of crystal form C:

about 15mg of the compound of formula (I) and an equimolar amount of Tris (3 mg) were weighed into HPLC glass vials, 0.5mL of EtOH was added, respectively, and the resulting turbid solution was left to stand at room temperature for magnetic stirring (1000 rpm) for about 4 days, after which the solid was collected by centrifugation to give Compound C form of formula (II). The sample is converted into the E crystal form after being dried in the open air at room temperature.

Preparation of crystal form D:

about 15mg of compound A form of formula (II-1) was weighed into a 3mL vial, 1.0mL MeOH/MTBE (1, v/v) was added, and the supernatant was filtered after equilibrating with stirring at 50 ℃ for about 1 hour. And (3) placing the obtained supernatant in a biochemical incubator, cooling from 50 ℃ to 5 ℃ at the speed of 0.1 ℃/minute, keeping the temperature at 5 ℃, and collecting separated solids to obtain the compound D crystal form of the formula (II). The sample is converted into the E crystal form after being dried in the open air at room temperature.

Preparation of crystal form E:

weighing about 15mg of the compound A crystal form of the formula (II-1) into an HPLC glass vial, adding 0.5mL of IPA respectively, magnetically stirring the obtained suspension (1000 rpm) under the condition of temperature cycle (40 ℃ -5 ℃,0.1 ℃/min, 2 cycles), and centrifuging to collect solids to obtain the compound E crystal form of the formula (II). ¹ H NMR(400MHz,CD ₃ OD)δppm 7.59-7.64(m,2H)7.50(t,J＝8.03Hz,1H)7.21(t,J＝10.16Hz,2H)7.06(d,J＝7.28Hz,1H)6.72-6.75(m,1H)6.68(d,J＝8.29Hz,1H)5.44(s,2H)5.21(qd,J＝7.03,3.01Hz,1H)4.55-4.73(m,3H)4.4 4(dt,J＝9.03,6.02Hz,1H)3.91-4.01(m,2H)3.68(s,6H)3.26(br s,2H)2.70-2.84(m,3H)2.63(br s,2H)2.40-2.54(m,1H)

Preparation of crystal form F:

about 15mg of compound a form of formula (II-1) was weighed into a 20mL vial and the solid was completely dissolved with 0.2-1.0 mL MeOH (undissolved sample filtered using 0.45 μm PTFE frit to give clear solution). To this clear solution MTBE was added dropwise with stirring (1000 rpm) until a solid precipitated, giving compound F of formula (II) as crystalline form. The sample is converted into the E crystal form after being dried in the open air at room temperature.

Preparation of a G crystal form:

weigh about 15mg of compound form a of formula (II-1) into a 3mL vial, add about 3mL EtOH to a 20mL vial, place the 3mL vial open into the 20mL vial, and seal the 20mL vial. Standing at room temperature for 7 days, and collecting solid to obtain the compound G crystal form of the formula (II). The sample is converted into the E crystal form after being dried in the open air at room temperature.

Preparation of crystal form H:

weigh about 15mg of compound form a of formula (II-1) into a 3mL vial, add about 3mL of THF to a 20mL vial, place the 3mL vial open into the 20mL vial, and seal the 20mL vial. Standing at room temperature for 7 days, and collecting solid to obtain the compound H crystal form of the formula (II). The sample is converted into the E crystal form after being dried in the open air at room temperature.

Preparation of form I:

weigh about 15mg of Compound A form of formula (II-1) into an HPLC glass vial, add 0.5mL of H each ₂ And O, magnetically stirring the obtained suspension (1000 rpm) under the condition of temperature cycle (40-5 ℃,0.1 ℃/min, 2 cycles), and centrifuging to collect a solid to obtain the crystal form I of the compound shown in the formula (II). The sample was converted to form E after open drying at room temperature.

Preparation of crystal form J:

weighing about 50mg of the compound shown in the formula (I) and dissolving the compound in 0.8mL of butanone, adding 0.9mL of 0.1mol/L phosphoric acid MEK solution at 50 ℃, dissolving and separating out the solid at 50 ℃, stirring for 1h at 50 ℃, and slowly reducing the temperature to 18 ℃ (about 0.5K/min); stirring at 18 deg.C for about 18h, filtering, and drying at 50 deg.C for 3-4h to obtain compound J crystal form of formula (III).

Preparation of crystal form K:

weighing about 50mg of the compound shown in the formula (I) and dissolving the compound in 0.4mL of butanone, adding 0.9mL of 0.1mol/L oxalic acid methanol solution at 50 ℃, dissolving the compound clearly at 50 ℃, and cooling to 18 ℃ without precipitation; adding 3.0mL of n-heptane, and layering; stirring at 18 deg.C for about 18h to precipitate solid, filtering, and drying at 50 deg.C for 3-4h to obtain compound K crystal form of formula (IV).

Preparation of the L crystal form:

weighing about 50mg of the compound of formula (I) and dissolving in 1.0mL of ethyl acetate, adding 8.43mg of oxalic acid solid at 50 ℃, separating out white solid at 50 ℃, and stirring for 1h at 50 ℃ to obtain oily substance; slowly reducing the temperature to 18 ℃; stirring at 18 deg.C for about 18h, transferring to solid, filtering, and drying at 50 deg.C for 3-4h to obtain compound L crystal form of formula (IV).

Preparation of the M crystal form:

weighing about 50mg of the compound of formula (I) and dissolving in 1.2mL of butanone, adding 10.18mg of maleic acid at 18 ℃ to precipitate a white solid, and continuing to stir for about 18h; filtering, and drying at 50 deg.C for 3-4h to obtain compound M crystal form of formula (V).

Preparation of N crystal form:

weighing about 50mg of the compound of formula (I) and dissolving in 0.4mL of butanone, adding 0.9mL of p-toluenesulfonic acid solution (0.1 mol/L methanol solution) at 18 ℃ and continuing to stir for about 18h; adding 1.0mL of N-heptane to precipitate a solid without precipitation, filtering, and drying at 50 ℃ for 3-4h to obtain the N crystal form of the compound of the formula (VI).

Preparation of crystal form O:

weighing about 50mg of the compound shown as the formula (I) and dissolving the compound in 0.8mL of butanone, adding 0.9mL of L-arginine solution (0.1 mol/L methanol solution) at 18 ℃, dissolving the compound clearly, quickly separating out white solid, and continuously stirring for about 18 hours; filtering, and drying the solid at 50 ℃ for 3-4h to obtain the compound O crystal form of the formula (VII). ¹ H NMR(400MHz,CD3OD)δppm 7.60(t,J＝7.78Hz,1H)7.57(s,1H)7.48(t,J＝8.11Hz,1H)7.15-7.23(m,2H)7.04(d,J＝7.45Hz,1H)6.71(br s,1H)6.66(d,J＝8.33Hz,1H)5.42(s,2H)5.13-5.24(m,1H)4.51-4.71(m,3H)4.41(dt,J＝9.15,5.95Hz,1H)3.87-4.06(m,3H)3.82(dd,J＝4.82,1.75Hz,1H)3.73-3.80(m,1H)3.60-3.71(m,3H)3.24(br s,2H)3.15(d,J＝6.14Hz,2H)2.76-2.84(m,2H)2.66-2.75(m,4H)2.61(br s,2H)2.40-2.52(m,1H)。

Preparation of crystal form P:

weighing about 50mg of the compound of the formula (I) and dissolving the compound in 1.4mL of acetonitrile, adding 0.9mL of L-arginine solution (0.1 mol/L of methanol solution) at 18 ℃, dissolving the compound clearly, quickly separating out white solid, and continuously stirring for about 18 hours; filtering, and drying the solid at 50 ℃ for 3-4h to obtain the compound P crystal form of the formula (VII).

Preparation of crystal form Q:

weighing about 50mg of the compound of formula (I) and dissolving in 1.0mL of acetonitrile, adding 0.9mL of meglumine solution (0.1 mol/L methanol solution) at 18 ℃, dissolving to be clear, adding 2.0mL of methyl tert-butyl ether, stirring for about 10min, separating out a solid, and continuing to stir for about 18h; filtering, and drying the solid at 50 ℃ for 3-4h to obtain the compound Q crystal form of the formula (VIII).

Preparation of crystal form R:

about 50mg of the compound of formula (I) was weighed and dissolved in 0.6mL tetrahydrofuran, 0.8mL acetonitrile was slowly added to the solution at 17 ℃, and a solid precipitated and filtered to give the compound of formula (I) R form.

Preparation of S crystal form:

weighing about 50mg of the compound shown as the formula (I) and dissolving the compound in 0.2mL of tetrahydrofuran at 50 ℃, stirring the mixture for a period of time at 50 ℃, cooling the mixture to 20 ℃ at a certain cooling rate, separating out solids, and filtering the mixture to obtain the S crystal form of the compound shown as the formula (I).

Preparation of crystal form T:

weighing about 50mg of the compound of formula (I), adding 0.8mL of methanol, maintaining the system in a suspended and stirred state at 20 ℃, and filtering the solid after a period of time to obtain the compound T crystal form of formula (I-1).

Preparation of a U crystal form:

weighing about 50mg of the compound of formula (I), adding 0.8mL of ethyl acetate, maintaining the system in a suspension and stirring state at 20 ℃, and filtering the solid after a period of time to obtain the compound U crystal form of formula (I-1).

Preparation of crystal form V:

about 50mg of the compound of formula (I) is weighed, 0.6mL acetonitrile is added, the system is maintained in a suspended and stirred state at 50 ℃, and after a period of time the solid is filtered to obtain the compound of formula (I) form V.

Example 3: study of hygroscopicity of crystalline forms

An SMS Intrasic dynamic vapor adsorption instrument is adopted to respectively take 10mg of crystal form A of the compound shown in the formula (II-1), 10mg of crystal form E of the compound shown in the formula (II) and 10mg of crystal form Q of the compound shown in the formula (VIII) to be placed in a DVS sample plate for testing. The specific results are shown in DVS spectrogram 27-29.

As can be seen from the above, the compound A of the formula (II-1) had a hygroscopic weight gain of 2.20% at 25 ℃ and 80% RH. The crystal form changes before and after adsorption and desorption. Compound E of formula (II) has a hygroscopic increase of 2.20% in crystal form at 25 ℃ and 80% RH. The crystal form changes before and after adsorption and desorption. The compound of formula (VIII) form Q has a moisture pick-up weight gain of 1.08% at 25 ℃ and 80% RH, slightly hygroscopic. The crystal form is unchanged before and after adsorption and desorption.

Example 4: solid stability Studies of Compound E crystalline form of formula (II)

Compound E of formula (II) was weighed as 500mg form, placed at the bottom of a glass sample bottle and spread into a thin layer. The samples were placed under accelerated conditions (40 ℃/75% RH and 60 ℃/75% RH) and were fully exposed. XRPD was measured on the sample at 5 days, 15 days, 1 month, and 2 months after placement, and the results were compared to the initial test results at 0 days, as shown in table 23 below:

table 23 solid stability study results of form E

And (4) conclusion: the compound E crystal form in the formula (II) has good stability.

Example 5: solid stability Studies of Crystal form Q of Compound of formula (VIII)

500mg of compound Q of formula (VIII) is weighed out and placed at the bottom of a glass sample bottle and spread into a thin layer. The samples were placed under accelerated conditions (40 ℃/75% RH and 60 ℃/75% RH) and were fully exposed. The sample was sampled at 1 month on

day

5, 15 days for XRPD detection and the results compared to the initial test results at day 0, as shown in table 24 below:

table 24 solid stability study results of crystal form Q

And (4) conclusion: the compound Q crystal form of the formula (VIII) has good stability.

Experimental example 1 in vitro cell Activity test

1. Material

1) Cell line the cell was constructed by Shanghai medicine Mingkude New medicine Kaiki Co., ltd. The details are given in the table below.

Target spot	Host cell
		GLP-1	HEK293

2) Reagent

cAMP Detection Kit,Cisbio(Cat#62AM4PEJ)
	1M HEPES,Invitrogen(Cat#15630-106)
1X HBSS,Invitrogen(Cat#14025)
	BSA,Sigma(Cat#B2064)
IBMX,Sigma(Cat#I5879)
	Exenatide, hao Yuan (HY-13443A)

3) Instrument for measuring the position of a moving object

OptiPlate-384,White,PerkinElmer(Cat#6007290)；384 well plate for Echo,Labcyte(Cat#P-05525)；EnVision,PerkinElmer；Vi-cell counter,Beckman(Cat#Vi-CELL ^TM XR Cell Viability Analyzer)

4) Compound information

Compounds were formulated with DMSO at a working concentration of 30 μ M. In this test, the amount of each sample used was 5. Mu.L.

2. Method for producing a composite material

1) Experimental Material

Experimental buffer solution

The pH was adjusted to 7.4 and made up to 25mL with HBSS 1 ×.

Preparation of detection reagent

Preparation of cAMP detection reagent: add 250. Mu.L of cAMP-D2, 250. Mu.L of anti-cAMP cryptate reagent to 4mL lysine buffer and mix gently.

2) Experimental methods

a) Preparation of compound plates:

the test compound was diluted 3-fold in 10 points at an initial concentration of 30 μ M and Bravo was used to complete the dilution.

The reference compound, exenatide, was diluted 10 points 3-fold, starting at 500nM and bravo.

b) Transfer compound:

1) Transfer 100nL of compound to the OptiPlate-384 plate using Echo.

2) The OptiPlate-384 plate was centrifuged at 1000rpm for 5 seconds.

c) Preparation of cell suspensions

1) A GLP-1 cell cryopreservation tube is quickly placed in warm water at 37 ℃ for thawing.

2) The cell suspension was transferred to a Transfer15 mL centrifuge tube and gently rinsed with 10mL HBSS.

3) The tube was centrifuged at 1000rpm for 1 minute at room temperature.

4) The supernatant was discarded.

5) The bottom cells were gently broken up and gently rinsed with 10mL HBSS, the cells were pelleted by centrifugation and finally resuspended in assay buffer.

6) Cell density and activity were measured using Vi-cells.

7) Dilution of GLP-1 cell concentration to 2.0 x 10 with assay buffer ⁵ /mL。

8) 100nL of diluted cell suspension was transferred in the OptiPlate-384 plate.

9) Incubate for 30 minutes at room temperature.

d) Adding a detection reagent:

1) To the OptiPlate-384 plate wells, 10. Mu.L of 800nM diluted cAMP standards were added in a gradient.

2) Add 10. Mu.L CAMP detection reagent.

3) The OptiPlate-384 plate was covered with TopSeal-A film and incubated for 60 min at room temperature.

TopSeal-A was removed and read at EnVision.

The results are shown in Table 25:

TABLE 25 in vitro cell Activity test results

Compound (I)	Human-GLP1，EC ₅₀ (nM)
		A compound of the formula (O)	0.37

And (4) conclusion: the compounds of the invention exhibit superior agonistic activity at the GLP-1 receptor.

Experimental example 2, in vivo DMPK study in rats:

the purpose of the experiment is as follows:

male SD rats were used as test animals, and the compound blood concentration was measured and pharmacokinetic behavior was evaluated after a single administration.

And (3) experimental operation:

healthy adult male SD rats 2 were selected as the oral group only. Oral group vehicle 20% PEG400/10% solutol/70% water, after mixing the test compound with the vehicle, vortexed and sonicated, a 0.5mg/mL clear solution is prepared. After 5mg/kg oral administration to rats, whole blood was collected for a certain period of time, plasma was prepared, the drug concentration was analyzed by LC-MS/MS method, and the drug parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The results are shown in Table 26:

TABLE 26 PK test results for compounds of the invention

Compound numbering	C _max (nM)	AUC _0-last (h*nmol/L)	F％
				A compound of the formula (O)	85.5	234	6.6％
Compound of formula (II-1) A crystal form	174	476	11.5％
				Crystal form Q of compound of formula (VIII)	185	530	13.6％

Note: PEG represents polyethylene glycol; solutol represents polyethylene glycol-15 hydroxystearate; c _max Is the maximum concentration; AUC _0-last Dose is the Dose of the drug for 24 hours of oral administration; f% is oral bioavailability.

And (4) conclusion: the crystal form of the compound shows higher oral exposure and better oral bioavailability, and shows good pharmacokinetic characteristics of oral medicines.

Experimental example 3, cynomolgus monkey in vivo DMPK study:

the purpose of the experiment is as follows:

male cynomolgus monkeys were used as test animals, and the plasma concentrations of the compounds were measured after a single administration and pharmacokinetic behavior was evaluated.

And (3) experimental operation:

healthy male cynomolgus 2 was selected as one group. The vehicle in the oral group is 20% HP-beta-CD water solution. After the compound to be tested is mixed with the solvent, vortex and ultrasonic treatment are carried out, and an approximately clear solution of 4mg/mL is prepared. The dosage of oral administration of cynomolgus monkey is 20mg/kg, after oral administration, whole blood is collected for a certain period of time, plasma is prepared, the concentration of the drug is analyzed by LC-MS/MS method, and the drug substitution parameter is calculated by Phoenix WinNonlin software (Pharsight company, USA). The results are shown in Table 27:

TABLE 27 PK test results for compounds of the invention

Note: HP-beta-CD represents hydroxypropyl-beta-cyclodextrin; c _max Is the maximum concentration; AUC _0-last 24 hour exposure for oral administration; and F% is oral bioavailability.

And (4) conclusion: the crystal form of the compound shows higher oral exposure and better oral bioavailability, the in-vivo exposure of the crystal form is obviously higher than that of a free state, and the compound shows good pharmacokinetic characteristics of an oral medicament.

Claims

1. Compounds of formula (O) or formula (I) and their pharmaceutically acceptable salts,

wherein s is selected from 0 to 3,

2. A pharmaceutically acceptable salt according to claim 1, wherein the chemical molar ratio of the compound to the acid or base molecule is 1: 2-2: 1, preferably 1: 2. 1: 1. 2:1.

3. a process for preparing a compound according to claim 1 or 2, comprising: a step of salifying the compound of formula (I) with an acid or a base;

preferably, the solvent used for the salt-forming reaction is selected from: at least one of butanone, methanol, ethanol, tetrahydrofuran, ethyl acetate, isopropanol, acetonitrile, and methyl tert-butyl ether.

4. A pharmaceutical composition comprising a pharmaceutically acceptable salt of claim 1 and optionally a pharmaceutically acceptable excipient.

5. Use of a pharmaceutically acceptable salt according to claim 1 for the preparation of a medicament for the prevention and/or treatment of metabolic disorders, preferably diabetes, obesity, non-alcoholic fatty liver disease.

6. A compound of the formula (II),

/>

wherein n is selected from 0 to 12, preferably from 0 to 8, preferably from 0 to 5, preferably from 0 to 3, preferably n is selected from 0, 1/2, 2/3, 1, 2, 2.7 and 3.

7. The compound of claim 6, the compound of formula (II) having the structure:

8. form a of a compound of formula (II-1) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 11.1426 +/-0.2000 degrees, 14.4804 +/-0.2000 degrees, 21.4921 +/-0.2000 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 11.1426 +/-0.2000 degrees, 14.4804 +/-0.2000 degrees, 17.7642 +/-0.2000 degrees, 19.6235 +/-0.2000 degrees, 21.4921 +/-0.2000 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 11.1426 +/-0.2000 degrees, 14.4804 +/-0.2000 degrees, 17.0921 +/-0.2000 degrees, 17.7642 +/-0.2000 degrees, 19.6235 +/-0.2000 degrees, 20.4359 +/-0.2000 degrees, 21.4921 +/-0.2000 degrees, 22.8874 +/-0.2000 degrees; preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.6759 °,10.2572 °,11.1426 °,14.4804 °,16.2701 °,17.0921 °,17.7642 °,19.6235 °,20.4359 °,20.9310 °,21.4921 °,22.8874 °,25.1971 °,26.5995 °,27.9955 °,28.6836 °,29.4212 °,30.9896 °.

9. The crystalline form a according to claim 8, having an XRPD pattern substantially as shown in figure 1; or

The differential scanning calorimetry curve has peak values of an endothermic peak at 76.0 +/-3.0 ℃ and 130.3 +/-3.0 ℃ respectively; or

A DSC profile substantially as shown in figure 2; or alternatively

The weight loss of the thermogravimetric analysis curve reaches 2.43 percent at 150.0 +/-3.0 ℃; or

The TGA profile is substantially as shown in figure 3.

10. Form E of a compound of formula (II), characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 θ angles: 18.8216 +/-0.2000 degrees, 20.0568 +/-0.2000 degrees, 25.1936 +/-0.2000 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 10.8415 +/-0.2000 degrees, 13.3963 +/-0.2000 degrees, 18.8216 +/-0.2000 degrees, 20.0568 +/-0.2000 degrees and 25.1936 +/-0.2000 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 10.3742 +/-0.2000 degree, 10.8415 +/-0.2000 degree, 13.3963 +/-0.2000 degree, 16.1259 +/-0.2000 degree, 18.8216 +/-0.2000 degree, 20.0568 +/-0.2000 degree, 20.7958 +/-0.2000 degree, 25.1936 +/-0.2000 degree; preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.3759 deg., 10.3742 deg., 10.8415 deg., 11.5008 deg., 13.3963 deg., 15.7418 deg., 16.1259 deg., 16.6392 deg., 17.2881 deg., 18.8216 deg., 19.2577 deg., 20.0568 deg., 20.7958 deg., 21.4850 deg., 22.1639 deg., 23.0777 deg., 24.1467 deg., 24.6828 deg., 25.1936 deg., 25.5960 deg., 26.2392 deg., 26.7365 deg., 27.1146 deg., 27.8176 deg., 28.5679 deg., 29.6443 deg., 30.8753 deg., 33.0123 deg., 33.8173 deg., 36.5754 deg..

11. The crystalline form E according to claim 10 having an XRPD pattern substantially as shown in figure 7; or

The differential scanning calorimetry curve has peak values of endothermic peaks at 91.0 + -3.0 deg.C and 149.9 + -3.0 deg.C respectively; or

A DSC profile substantially as shown in figure 8; or

The weight loss of the thermogravimetric analysis curve reaches 6.37 percent at 150.0 +/-3.0 ℃; or

The TGA profile is substantially as shown in figure 9.

12. Form J of the compound of formula (III) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 6.763 plus or minus 0.200 degree, 13.619 plus or minus 0.200 degree, 18.128 plus or minus 0.200 degree,

wherein i is selected from 0 to 2.

13. The crystalline form J of claim 12 having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 6.763 plus or minus 0.200 degree, 13.619 plus or minus 0.200 degree, 15.848 plus or minus 0.200 degree, 18.128 plus or minus 0.200 degree, 24.643 plus or minus 0.200 degree;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 6.763 +/-0.200 degrees, 13.619 +/-0.200 degrees, 15.848 +/-0.200 degrees, 18.128 +/-0.200 degrees, 19.438 +/-0.200 degrees, 21.422 +/-0.200 degrees, 22.621 +/-0.200 degrees, 24.643 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 6.763 °,9.065 °,9.535 °,11.902 °,12.066 °,12.874 °,13.619 °,14.169 °,14.918 °,15.848 °,16.105 °,16.573 °,17.620 °,18.128 °,18.510 °,18.826 °,19.107 °,19.438 °,20.538 °,21.191 °,21.422 °,21.794 °,22.416 °,22.621 °,22.806 °,23.376 °,23.609 °,24.643 °,25.149 °,25.650 °,27.329 °, 28.368 °,29.916 °,30.162 °,31.416 °,33.040 °,33.684 °,35.327 °,37.570 °.

14. The crystalline form J of claim 12 having an XRPD pattern substantially as shown in figure 14.

15. A compound of the formula (IV),

wherein m is selected from 0 to 2.

16. Crystalline form K of a compound of formula (IV-1), characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 16.860 +/-0.200 degrees, 18.189 +/-0.200 degrees, 20.709 +/-0.200 degrees,

17. form K according to claim 16 having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 9.972 +/-0.200 degrees, 16.860 +/-0.200 degrees, 18.189 +/-0.200 degrees, 20.709 +/-0.200 degrees and 23.950 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 4.581 +/-0.200 degrees, 9.972 +/-0.200 degrees, 10.392 +/-0.200 degrees, 16.860 +/-0.200 degrees, 18.189 +/-0.200 degrees, 20.709 +/-0.200 degrees, 23.950 +/-0.200 degrees, 26.841 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 4.581 °,6.439 °,9.972 °,10.232 °,10.392 °,13.328 °,14.053 °,14.696 °,16.860 °,18.189 °,20.709 °,22.766 °,23.950 °,25.785 °,26.841 °.

18. The crystalline form K of claim 16 having an XRPD pattern substantially as shown in figure 15.

19. A crystalline form L of a compound of formula (IV) characterised by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 18.726 plus or minus 0.200 degree, 21.044 plus or minus 0.200 degree, 24.648 plus or minus 0.200 degree;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 6.494 plus or minus 0.200 degree, 18.726 plus or minus 0.200 degree, 19.547 plus or minus 0.200 degree, 21.044 plus or minus 0.200 degree, 24.648 plus or minus 0.200 degree;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 6.494 +/-0.200 degrees, 15.366 +/-0.200 degrees, 17.885 +/-0.200 degrees, 18.726 +/-0.200 degrees, 19.547 +/-0.200 degrees, 21.044 +/-0.200 degrees, 24.648 +/-0.200 degrees, 27.453 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.797 °,6.494 °,7.655 °,10.474 °,13.036 °,13.388 °,15.366 °,16.235 °,17.885 °,18.726 °,19.547 °,21.044 °,24.368 °,24.648 °,27.453 °.

20. The crystalline form L according to claim 19, having an XRPD pattern substantially as shown in figure 16.

21. A compound of the formula (V),

wherein o is selected from 0 to 2.

22. A crystalline form M of a compound of formula (V) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 5.682 +/-0.200 degrees, 11.389 +/-0.200 degrees, 17.202 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.682 +/-0.200 degrees, 11.389 +/-0.200 degrees, 16.009 +/-0.200 degrees, 17.202 +/-0.200 degrees and 29.418 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.682 +/-0.200 degrees, 11.389 +/-0.200 degrees, 16.009 +/-0.200 degrees, 17.202 +/-0.200 degrees, 17.854 +/-0.200 degrees, 24.147 +/-0.200 degrees, 25.302 +/-0.200 degrees, 29.418 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.682 °,10.619 °,11.389 °,12.280 °,12.637 °,14.434 °,15.764 °,16.009 °,17.202 °,17.854 °,18.783 °,19.352 °,20.673 °,21.044 °,21.729 °,22.632 °,23.341 °,24.147 °,25.302 °,26.982 °,28.950 °,29.418 °,30.123 °,33.086 °.

23. The crystalline form M of claim 22 having an XRPD pattern substantially as shown in figure 17.

24. A compound of the formula (VI),

25. an N crystalline form of a compound of formula (VI) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 11.439 +/-0.200 degrees, 18.363 +/-0.200 degrees, 28.859 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 11.439 +/-0.200 degrees, 18.363 +/-0.200 degrees, 20.062 +/-0.200 degrees, 22.657 +/-0.200 degrees and 28.859 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 8.581 +/-0.200 degrees, 11.439 +/-0.200 degrees, 18.363 +/-0.200 degrees, 20.062 +/-0.200 degrees, 22.657 +/-0.200 degrees, 23.664 +/-0.200 degrees, 25.356 +/-0.200 degrees, 28.859 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.697 °,8.581 °,8.801 °,11.439 °,12.051 °,12.568 °,13.226 °,14.357 °,14.846 °,15.655 °,16.120 °,17.223 °,17.880 °,18.363 °,18.914 °,19.236 °,20.062 °,20.397 °,21.454 °,22.657 °,22.991 °,23.664 °,24.391 °,24.844 °,25.356 °,26.003 °,26.573 °,26.956 °,27.309 °, 28.914 °,28.859 °,29.089 °,29.935 °,31.553 °,31.847 °,32.174 °,32.715 °,34.782 °,38.569 °.

26. The crystalline form N according to claim 25, having an XRPD pattern substantially as shown in figure 18.

27. A compound of the formula (VII),

wherein p is selected from 0 to 3.

28. Crystalline O form of a compound of formula (VII) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 9.485 plus or minus 0.200 degrees, 11.273 plus or minus 0.200 degrees, 17.536 plus or minus 0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 9.485 plus or minus 0.200 degrees, 11.273 plus or minus 0.200 degrees, 12.495 plus or minus 0.200 degrees, 17.536 plus or minus 0.200 degrees and 18.874 plus or minus 0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 9.485 plus or minus 0.200 degrees, 11.273 plus or minus 0.200 degrees, 12.495 plus or minus 0.200 degrees, 15.005 plus or minus 0.200 degrees, 17.536 plus or minus 0.200 degrees, 18.874 plus or minus 0.200 degrees, 19.568 plus or minus 0.200 degrees, 20.291 plus or minus 0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 4.859 °,7.487 °,9.485 °,10.000 °,11.273 °,12.495 °,12.842 °,14.649 °,15.005 °,16.766 °,17.536 °,18.874 °,19.568 °,20.082 °,20.291 °,21.189 °,22.679 °,23.508 °,25.140 °,25.788 °,28.081 °,29.067 °,29.739 °,31.639 °,35.581 °.

29. The crystalline form O of claim 28 having an XRPD pattern substantially as shown in figure 19.

30. A crystalline form P of a compound of formula (VII) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 12.481 plus or minus 0.200 degree, 14.965 plus or minus 0.200 degree, 17.480 plus or minus 0.200 degree;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 9.998 +/-0.200 degrees, 12.481 +/-0.200 degrees, 14.965 +/-0.200 degrees, 17.480 +/-0.200 degrees, 19.969 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 5.007 °,7.512 °,9.604 °,9.998 °,12.481 °,14.965 °,17.480 °,18.908 °,19.969 °,20.933 °,25.629 °,27.587 °,35.375 °.

31. The crystalline form P of claim 30 having an XRPD pattern substantially as shown in figure 20.

32. A compound of the formula (VIII),

33. crystalline form Q of a compound of formula (VIII) characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 6.123 +/-0.200 degrees, 9.130 +/-0.200 degrees, 12.123 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 6.123 +/-0.200 degrees, 9.130 +/-0.200 degrees, 12.123 +/-0.200 degrees, 20.095 +/-0.200 degrees and 22.942 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 6.123 +/-0.200 degrees, 9.130 +/-0.200 degrees, 12.123 +/-0.200 degrees, 15.071 +/-0.200 degrees, 18.151 +/-0.200 degrees, 20.095 +/-0.200 degrees, 22.045 +/-0.200 degrees, 22.942 +/-0.200 degrees;

preferably, the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 6.123 °,7.677 °,9.130 °,10.013 °,11.598 °,12.123 °,14.770 °,15.071 °,15.986 °,16.493 °,16.692 °,17.365 °,18.151 °,18.915 °,20.095 °,20.569 °,21.147 °,22.045 °,22.942 °,24.106 °,24.617 °,26.108 °,27.014 °,27.822 °,28.433 °,29.464 °,30.256 °,30.863 °,31.820 °,33.446 °,34.822 °,36.389 °,37.646 °,37.803 °.

34. The crystalline form Q according to claim 33, having an XRPD pattern substantially as shown in figure 21.

35. Use of a compound according to any one of claims 6, 7, 15, 21, 24, 27 or 32 or the form a according to claim 8 or 9 or the form E according to claim 10 or 11 or the form J according to any one of claims 12 to 14 or the form K according to any one of claims 16 to 18 or the form L according to claim 19 or 20 or the form M according to claim 22 or 23 or the form N according to claim 25 or 26 or the form O according to claim 28 or 29 or the form P according to claim 30 or 31 or the form Q according to claim 33 or 34 for the preparation of a medicament for the treatment of a metabolic disease.

36. A compound of the formula (III),

wherein i is selected from 0 to 2./>